Therapeutic compounds and methods of use thereof

ABSTRACT

The invention provides a compounds and salts that are sodium channel modulators, as well as compositions containing such a compound or salt and therapeutic methods for using such a compound, salt, or composition.

CROSS-REFERENCE TO RELATED APPLICATION(S)

This application is a divisional of Ser. No. 16/495,802, filed 19 Sep.2019, which is a 35 U.S.C. § 371 application of InternationalApplication No. PCT/US2018/023740, filed 22 Mar. 2018, and claimspriority to international patent application number PCT/CN2017/078017,filed 24 Mar. 2017. The entire content of international patentapplication number PCT/CN2017/078017 is hereby incorporated by referenceherein.

BACKGROUND

The present invention relates to organic compounds useful for therapy ina mammal, and in particular to inhibitors of sodium channel (e.g.,NaV1.7) that are useful for treating sodium channel-mediated diseases orconditions, such as pain, as well as other diseases and conditionsassociated with the modulation of sodium channels.

Voltage-gated sodium channels are transmembrane proteins that initiateaction potentials in nerve, muscle and other electrically excitablecells, and are a necessary component of normal sensation, emotions,thoughts and movements (Catterall, W. A., Nature (2001), Vol. 409, pp.988-990). These channels consist of a highly processed alpha subunitthat is associated with auxiliary beta subunits. The pore-forming alphasubunit is sufficient for channel function, but the kinetics and voltagedependence of channel gating are in part modified by the beta subunits(Goldin et al., Neuron (2000), Vol. 28, pp. 365-368).Electrophysiological recording, biochemical purification, and molecularcloning have identified ten different sodium channel alpha subunits andfour beta subunits (Yu, F. H., et al., Sci. STKE (2004), 253; and Yu, F.H., et al., Neurosci. (2003), 20:7577-85).

The sodium channel family of proteins has been extensively studied andshown to be involved in a number of vital body functions. Research inthis area has identified variants of the alpha subunits that result inmajor changes in channel function and activities, which can ultimatelylead to major pathophysiological conditions. The members of this familyof proteins are denoted NaV1.1 to NaV1.9.

NaV1.7 is a tetrodotoxin-sensitive voltage-gated sodium channel encodedby the gene SCN9A. Human NaV1.7 was first cloned from neuroendocrinecells (Klugbauer, N., et al., 1995 EMBO J., 14 (6): 1084-90.) and ratNaV1.7 was cloned from a pheochromocytoma PC12 cell line (Toledo-Aral,J. J., et al., Proc. Natl. Acad. Sci. USA (1997), 94:1527-1532) and fromrat dorsal root ganglia (Sangameswaran, L., et al., (1997), J. Biol.Chem., 272 (23): 14805-9). NaV1.7 is expressed primarily in theperipheral nervous system, especially nocieptors and olfactory neuronsand sympathetic neurons. The inhibition, or blocking, of NaV1.7 has beenshown to result in analgesic activity. Knockout of NaV1.7 expression ina subset of sensory neurons that are predominantly nociceptive resultsin resistance to inflammatory pain (Nassar, et al., op. cit.). Likewise,loss of function mutations in humans results in congenital indifferenceto pain (CIP), in which the individuals are resistant to bothinflammatory and neuropathic pain (Cox, J. J., et al., Nature (2006);444:894-898; Goldberg, Y. P., et al., Clin. Genet. (2007); 71:311-319).Conversely, gain of function mutations in NaV1.7 have been establishedin two human heritable pain conditions, primary erythromelalgia andfamilial rectal pain, (Yang, Y., et al., J. Med. Genet. (2004),41(3):171-4). In addition, a single nucleotide polymorphism (R1150W)that has very subtle effects on the time- and voltage-dependence ofchannel gating has large effects on pain perception (Estacion, M., etal., 2009. Ann Neurol 66: 862-6; Reimann, F., et al., Proc Natl Acad SciUSA (2010), 107: 5148-53). About 10% of the patients with a variety ofpain conditions have the allele conferring greater sensitivity to painand thus might be more likely to respond to block of NaV1.7. BecauseNaV1.7 is expressed in both sensory and sympathetic neurons, one mightexpect that enhanced pain perception would be accompanied bycardiovascular abnormalities such as hypertension, but no correlationhas been reported. Thus, both the CIP mutations and SNP analysis suggestthat human pain responses are more sensitive to changes in NaV1.7currents than are perturbations of autonomic function.

Sodium channel blockers have been shown to be useful in the treatment ofpain, (see, e.g., Wood, J. N., et al., J. Neurobiol. (2004), 61(1),55-71. Genetic and functional studies have provided evidence to supportthat activity of NaV1.7 as a major contributor to pain signalling inmammals. (See Hajj, et al. Nature Reviews Neuroscience; 2013, vol 14,49-62; and Lee, et al. Cell; 2014, vol 157; 1-12). Presently, there area limited number of effective sodium channel blockers for the treatmentof pain with a minimum of adverse side effects which are currently inthe clinic. Thus there remains a need for selective voltage-gated sodiumchannel modulators (e.g., modulators of NaV1.7) that can provide agreater therapeutic index for treatment. There is also a need forselective voltage-gated sodium channel modulators that have potent invivo activity and that have good metabolic stability.

SUMMARY OF THE INVENTION

In one aspect the present invention provides novel compounds havingsodium channel blocking activity that are useful for the treatment ofpain. Certain compounds of the invention have potent in vivo activityand good metabolic stability.

In a first embodiment, the invention provides a compound of formula Ithat is selected from the group consisting of:

-   (S)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;-   (S)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;-   (S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide;    and-   (S)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;    or a pharmaceutically acceptable thereof.

In another aspect the present invention provides for a pharmaceuticalcomposition comprising a compound of formula I or a pharmaceuticallyacceptable salt thereof, and a pharmaceutically acceptable excipient.

In another aspect the present invention provides a method of treating adisease or condition in a mammal selected from the group consisting ofpain, depression, cardiovascular diseases, respiratory diseases, andpsychiatric diseases, and combinations thereof, comprising administeringto the mammal a therapeutically effective amount of a compound offormula I or a pharmaceutically acceptable salt thereof. In anotheraspect of the present invention said disease or condition is selectedfrom the group consisting of neuropathic pain, inflammatory pain,visceral pain, cancer pain, chemotherapy pain, trauma pain, surgicalpain, post-surgical pain, childbirth pain, labor pain, neurogenicbladder, ulcerative colitis, chronic pain, persistent pain, peripherallymediated pain, centrally mediated pain, chronic headache, migraineheadache, sinus headache, tension headache, phantom limb pain, dentalpain, peripheral nerve injury or a combination thereof. In anotheraspect of the present invention said disease or condition is selectedfrom the group consisting of pain associated with HIV, HIV treatmentinduced neuropathy, trigeminal neuralgia, post-herpetic neuralgia,eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome,Crohns disease, pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheralneuropathy, arthritis, rheumatoid arthritis, osteoarthritis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,malignant hyperthermia, cystic fibrosis, pseudoaldosteronism,rhabdomyolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxin related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscause by stroke or neural trauma, tach-arrhythmias, atrial fibrillationand ventricular fibrillation.

In another aspect the present invention provides for a method oftreating pain in a mammal by the inhibition of ion flux through avoltage-dependent sodium channel in the mammal, wherein the methodcomprises administering to the mammal a therapeutically effective amountof a compound of formula I or a pharmaceutically acceptable saltthereof.

In another aspect the present invention provides for a method ofdecreasing ion flux through a voltage-dependent sodium channel in a cellin a mammal, wherein the method comprises contacting the cell with acompound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a method oftreating pruritus in a mammal, wherein the method comprisesadministering to the mammal a therapeutically effective amount of acompound of formula I or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a method oftreating cancer in a mammal, wherein the method comprises administeringto the mammal a therapeutically effective amount a compound of formula Ior a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a method oftreating, but not preventing, pain in a mammal, wherein the methodcomprises administering to the mammal a therapeutically effective amountof a compound of formula I or a pharmaceutically acceptable saltthereof. In another aspect of the present invention the pain is selectedfrom the group consisting of neuropathic pain, inflammatory pain,visceral pain, cancer pain, chemotherapy pain, trauma pain, surgicalpain, post-surgical pain, childbirth pain, labor pain, neurogenicbladder, ulcerative colitis, chronic pain, persistent pain, peripherallymediated pain, centrally mediated pain, chronic headache, migraineheadache, sinus headache, tension headache, phantom limb pain, dentalpain, peripheral nerve injury or a combination thereof. In anotheraspect the present invention the pain is associated with a disease orcondition selected from the group consisting of HIV, HIV treatmentinduced neuropathy, trigeminal neuralgia, post-herpetic neuralgia,eudynia, heat sensitivity, tosarcoidosis, irritable bowel syndrome,Crohns disease, pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), diabetic neuropathy, peripheralneuropathy, arthritis, rheumatoid arthritis, osteoarthritis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,malignant hyperthermia, cystic fibrosis, pseudoaldosteronism,rhabdomyolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxin related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscause by stroke or neural trauma, tach-arrhythmias, atrial fibrillationand ventricular fibrillation.

In another aspect the present invention provides for a method for thetreatment or prophylaxis of pain, depression, cardiovascular disease,respiratory disease, or psychiatric disease, or a combinations thereof,in an animal which method comprises administering an effective amount ofa compound of formula I, or a pharmaceutically acceptable salt thereof.

In another aspect the present invention provides for a compound offormula I, or a pharmaceutically acceptable salt thereof for the use asa medicament for the treatment of diseases and disorders selected fromthe group consisting of pain, depression, cardiovascular diseases,respiratory diseases, and psychiatric diseases, or a combinationthereof.

In another aspect the present invention provides for the use of acompound of formula I, or a pharmaceutically acceptable salt thereof forthe manufacture of a medicament for the treatment of diseases anddisorders selected from the group consisting of pain, depression,cardiovascular diseases, respiratory diseases, and psychiatric diseases,or a combination thereof.

In another aspect the present invention provides for the invention asdescribed herein.

DETAILED DESCRIPTION OF THE INVENTION Definitions

As used herein, the term “chiral” refers to molecules which have theproperty of non-superimposability of the mirror image partner, while theterm “achiral” refers to molecules which are superimposable on theirmirror image partner.

As used herein, the term “stereoisomers” refers to compounds which haveidentical chemical constitution, but differ with regard to thearrangement of the atoms or groups in space.

As used herein a wavy line “

” that intersects a bond in a chemical structure indicates the point ofattachment of the bond that the wavy bond intersects in the chemicalstructure to the remainder of a molecule.

“Diastereomer” refers to a stereoisomer with two or more centers ofchirality and whose molecules are not mirror images of one another.Diastereomers have different physical properties, e.g. melting points,boiling points, spectral properties, and reactivities. Mixtures ofdiastereomers can separate under high resolution analytical proceduressuch as electrophoresis and chromatography.

“Enantiomers” refer to two stereoisomers of a compound which arenon-superimposable mirror images of one another.

Stereochemical definitions and conventions used herein generally followS. P. Parker, Ed., McGraw-Hill Dictionary of Chemical Terms (1984)McGraw-Hill Book Company, New York; and Eliel, E. and Wilen, S.,“Stereochemistry of Organic Compounds”, John Wiley & Sons, Inc., NewYork, 1994. The compounds of the invention can contain asymmetric orchiral centers, and therefore exist in different stereoisomeric forms.It is intended that all stereoisomeric forms of the compounds of theinvention, including but not limited to, diastereomers, enantiomers andatropisomers, as well as mixtures thereof such as racemic mixtures, formpart of the present invention. Many organic compounds exist in opticallyactive forms, i.e., they have the ability to rotate the plane ofplane-polarized light. In describing an optically active compound, theprefixes D and L, or R and S, are used to denote the absoluteconfiguration of the molecule about its chiral center(s). The prefixes dand 1 or (+) and (−) are employed to designate the sign of rotation ofplane-polarized light by the compound, with (−) or 1 meaning that thecompound is levorotatory. A compound prefixed with (+) or d isdextrorotatory. For a given chemical structure, these stereoisomers areidentical except that they are mirror images of one another. A specificstereoisomer can also be referred to as an enantiomer, and a mixture ofsuch isomers is often called an enantiomeric mixture. A 50:50 mixture ofenantiomers is referred to as a racemic mixture or a racemate, which canoccur where there has been no stereoselection or stereospecificity in achemical reaction or process. The terms “racemic mixture” and “racemate”refer to an equimolar mixture of two enantiomeric species, devoid ofoptical activity.

When a bond in a compound formula herein is drawn in anon-stereochemical manner (e.g. flat), the atom to which the bond isattached includes all stereochemical possibilities. When a bond in acompound formula herein is drawn in a defined stereochemical manner(e.g. bold, bold-wedge, dashed or dashed-wedge), it is to be understoodthat the atom to which the stereochemical bond is attached is enrichedin the absolute stereoisomer depicted unless otherwise noted. In oneembodiment, the compound may be at least 51% the absolute stereoisomerdepicted. In another embodiment, the compound may be at least 80% theabsolute stereoisomer depicted. In another embodiment, the compound maybe at least 90% the absolute stereoisomer depicted. In anotherembodiment, the compound may be at least 95% the absolute stereoisomerdepicted. In another embodiment, the compound may be at least 97% theabsolute stereoisomer depicted. In another embodiment, the compound maybe at least 98% the absolute stereoisomer depicted. In anotherembodiment, the compound may be at least 99% the absolute stereoisomerdepicted.

As used herein, the term “tautomer” or “tautomeric form” refers tostructural isomers of different energies which are interconvertible viaa low energy barrier. For example, proton tautomers (also known asprototropic tautomers) include interconversions via migration of aproton, such as keto-enol and imine-enamine isomenzations. Valencetautomers include interconversions by reorganization of some of thebonding electrons.

As used herein, the term “solvate” refers to an association or complexof one or more solvent molecules and a compound of the invention.Examples of solvents that form solvates include, but are not limited to,water, isopropanol, ethanol, methanol, DMSO, ethyl acetate, acetic acid,and ethanolamine. The term “hydrate” refers to the complex where thesolvent molecule is water.

As used herein, the term “protecting group” refers to a substituent thatis commonly employed to block or protect a particular functional groupon a compound. For example, an “amino-protecting group” is a substituentattached to an amino group that blocks or protects the aminofunctionality in the compound. Suitable amino-protecting groups includeacetyl, trifluoroacetyl, t-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ)and 9-fluorenylmethylenoxycarbonyl (Fmoc). Similarly, a“hydroxy-protecting group” refers to a substituent of a hydroxy groupthat blocks or protects the hydroxy functionality. Suitable protectinggroups include acetyl and silyl. A “carboxy-protecting group” refers toa substituent of the carboxy group that blocks or protects the carboxyfunctionality. Common carboxy-protecting groups includephenylsulfonylethyl, cyanoethyl, 2-(trimethylsilyl)ethyl,2-(trimethylsilyl)ethoxymethyl, 2-(p-toluenesulfonyl)ethyl,2-(p-nitrophenylsulfenyl)ethyl, 2-(diphenylphosphino)-ethyl, nitroethyland the like. For a general description of protecting groups and theiruse, see P. G. M. Wuts and T. W. Greene, Greene's Protective Groups inOrganic Synthesis 4^(th) edition, Wiley-Interscience, New York, 2006.

As used herein, the term “mammal” includes, but is not limited to,humans, mice, rats, guinea pigs, monkeys, dogs, cats, horses, cows,pigs, and sheep.

As used herein, the term “pharmaceutically acceptable salts” is meant toinclude salts of the active compounds which are prepared with relativelynontoxic acids or bases, depending on the particular substituents foundon the compounds described herein. When compounds of the presentinvention contain relatively acidic functionalities, base addition saltscan be obtained by contacting the neutral form of such compounds with asufficient amount of the desired base, either neat or in a suitableinert solvent.

Examples of salts derived from pharmaceutically-acceptable inorganicbases include aluminum, ammonium, calcium, copper, ferric, ferrous,lithium, magnesium, manganic, manganous, potassium, sodium, zinc and thelike. Salts derived from pharmaceutically-acceptable organic basesinclude salts of primary, secondary and tertiary amines, includingsubstituted amines, cyclic amines, naturally-occurring amines and thelike, such as arginine, betaine, caffeine, choline,N,N′-dibenzylethylenediamine, diethylamine, 2-diethylaminoethanol,2-dimethylaminoethanol, ethanolamine, ethylenediamine,N-ethylmorpholine, N-ethylpiperidine, glucamine, glucosamine, histidine,hydrabamine, isopropylamine, lysine, methylglucamine, morpholine,piperazine, piperidine, polyamine resins, procaine, purines,theobromine, triethylamine, trimethylamine, tripropylamine, tromethamineand the like. When compounds of the present invention contain relativelybasic functionalities, acid addition salts can be obtained by contactingthe neutral form of such compounds with a sufficient amount of thedesired acid, either neat or in a suitable inert solvent. Examples ofpharmaceutically acceptable acid addition salts include those derivedfrom inorganic acids like hydrochloric, hydrobromic, nitric, carbonic,monohydrogencarbonic, phosphoric, monohydrogenphosphoric,dihydrogenphosphoric, sulfuric, monohydrogensulfuric, hydriodic, orphosphorous acids and the like, as well as the salts derived fromrelatively nontoxic organic acids like acetic, propionic, isobutyric,malonic, benzoic, succinic, suberic, fumaric, mandelic, phthalic,benzenesulfonic, p-tolylsulfonic, citric, tartaric, methanesulfonic, andthe like. Also included are salts of amino acids such as arginate andthe like, and salts of organic acids like glucuronic or galactunoricacids and the like (see, for example, Berge, S. M., et al.,“Pharmaceutical Salts”, Journal of Pharmaceutical Science, 1977, 66,1-19). Certain specific compounds of the present invention contain bothbasic and acidic functionalities that allow the compounds to beconverted into either base or acid addition salts.

The neutral forms of the compounds can be regenerated by contacting thesalt with a base or acid and isolating the parent compound in theconventional manner. The parent form of the compound differs from thevarious salt forms in certain physical properties, such as solubility inpolar solvents, but otherwise the salts are equivalent to the parentform of the compound for the purposes of the present invention.

In addition to salt forms, the present invention provides compoundswhich are in a prodrug form. As used herein the term “prodrug” refers tothose compounds that readily undergo chemical changes underphysiological conditions to provide the compounds of the presentinvention. Additionally, prodrugs can be converted to the compounds ofthe present invention by chemical or biochemical methods in an ex vivoenvironment. For example, prodrugs can be slowly converted to thecompounds of the present invention when placed in a transdermal patchreservoir with a suitable enzyme or chemical reagent.

Prodrugs of the invention include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three orfour) amino acid residues, is covalently joined through an amide orester bond to a free amino, hydroxy or carboxylic acid group of acompound of the present invention. The amino acid residues include butare not limited to the 20 naturally occurring amino acids commonlydesignated by three letter symbols and also includes phosphoserine,phosphothreonine, phosphotyrosine, 4-hydroxyproline, hydroxylysine,demosine, isodemosine, gamma-carboxyglutamate, hippuric acid,octahydroindole-2-carboxylic acid, statine,1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid, penicillamine,ornithine, 3-methylhistidine, norvaline, beta-alanine,gamma-aminobutyric acid, citrulline, homocysteine, homoserine,methyl-alanine, para-benzoylphenylalanine, phenylglycine,propargylglycine, sarcosine, methionine sulfone and tert-butylglycine.

Additional types of prodrugs are also encompassed. For instance, a freecarboxyl group of a compound of the invention can be derivatized as anamide or alkyl ester. As another example, compounds of this inventioncomprising free hydroxy groups can be derivatized as prodrugs byconverting the hydroxy group into a group such as, but not limited to, aphosphate ester, hemisuccinate, dimethylaminoacetate, orphosphoryloxymethyloxycarbonyl group, as outlined in Fleisher, D. etal., (1996) Improved oral drug delivery: solubility limitations overcomeby the use of prodrugs Advanced Drug Delivery Reviews, 19:115. Carbamateprodrugs of hydroxy and amino groups are also included, as are carbonateprodrugs, sulfonate esters and sulfate esters of hydroxy groups.Derivatization of hydroxy groups as (acyloxy)methyl and (acyloxy)ethylethers, wherein the acyl group can be an alkyl ester optionallysubstituted with groups including, but not limited to, ether, amine andcarboxylic acid functionalities, or where the acyl group is an aminoacid ester as described above, are also encompassed. Prodrugs of thistype are described in J. Med. Chem., (1996), 39:10. More specificexamples include replacement of the hydrogen atom of the alcohol groupwith a group such as (C₁₋₆)alkanoyloxymethyl,1-((C₁₋₆)alkanoyloxy)ethyl, 1-methyl-1-((C₁₋₆)alkanoyloxy)ethyl,(C₁₋₆)alkoxycarbonyloxymethyl, N—(C₁₋₆)alkoxycarbonylaminomethyl,succinoyl, (C₁₋₆)alkanoyl, alpha-amino(C₁₋₄)alkanoyl, arylacyl andalpha-aminoacyl, or alpha-aminoacyl-alpha-aminoacyl, where eachalpha-aminoacyl group is independently selected from the naturallyoccurring L-amino acids, P(O)(OH)₂, —P(O)(O(C₁₋₆)alkyl)₂ or glycosyl(the radical resulting from the removal of a hydroxyl group of thehemiacetal form of a carbohydrate).

For additional examples of prodrug derivatives, see, for example, a)Design of Prodrugs, edited by H. Bundgaard, (Elsevier, 1985) and Methodsin Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al.(Academic Press, 1985); b) A Textbook of Drug Design and Development,edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design andApplication of Prodrugs,” by H. Bundgaard p. 113-191 (1991); c) H.Bundgaard, Advanced Drug Delivery Reviews, 8:1-38 (1992); d) H.Bundgaard, et al., Journal of Pharmaceutical Sciences, 77:285 (1988);and e) N. Kakeya, et al., Chem. Pharm. Bull., 32:692 (1984), each ofwhich is specifically incorporated herein by reference.

Additionally, the present invention provides for metabolites ofcompounds of the invention. As used herein, a “metabolite” refers to aproduct produced through metabolism in the body of a specified compoundor salt thereof. Such products can result for example from theoxidation, reduction, hydrolysis, amidation, deamidation,esterification, deesterification, enzymatic cleavage, and the like, ofthe administered compound.

Metabolite products typically are identified by preparing aradiolabelled (e.g., ¹⁴C or ³H) isotope of a compound of the invention,administering it parenterally in a detectable dose (e.g., greater thanabout 0.5 mg/kg) to an animal such as rat, mouse, guinea pig, monkey, orto man, allowing sufficient time for metabolism to occur (typicallyabout 30 seconds to 30 hours) and isolating its conversion products fromthe urine, blood or other biological samples. These products are easilyisolated since they are labeled (others are isolated by the use ofantibodies capable of binding epitopes surviving in the metabolite). Themetabolite structures are determined in conventional fashion, e.g., byMS, LC/MS or NMR analysis. In general, analysis of metabolites is donein the same way as conventional drug metabolism studies well known tothose skilled in the art. The metabolite products, so long as they arenot otherwise found in vivo, are useful in diagnostic assays fortherapeutic dosing of the compounds of the invention.

Certain compounds of the present invention can exist in unsolvated formsas well as solvated forms, including hydrated forms. In general, thesolvated forms are equivalent to unsolvated forms and are intended to beencompassed within the scope of the present invention. Certain compoundsof the present invention can exist in multiple crystalline or amorphousforms. In general, all physical forms are equivalent for the usescontemplated by the present invention and are intended to be within thescope of the present invention.

Certain compounds of the present invention possess asymmetric carbonatoms (optical centers) or double bonds; the racemates, diastereomers,geometric isomers, regioisomers and individual isomers (e.g., separateenantiomers) are all intended to be encompassed within the scope of thepresent invention.

The terms “treat” and “treatment” refer to both therapeutic treatmentand/or prophylactic treatment or preventative measures, wherein theobject is to prevent or slow down (lessen) an undesired physiologicalchange or disorder, such as, for example, the development or spread ofcancer. For purposes of this invention, beneficial or desired clinicalresults include, but are not limited to, alleviation of symptoms,diminishment of extent of disease or disorder, stabilized (i.e., notworsening) state of disease or disorder, delay or slowing of diseaseprogression, amelioration or palliation of the disease state ordisorder, and remission (whether partial or total), whether detectableor undetectable. “Treatment” can also mean prolonging survival ascompared to expected survival if not receiving treatment. Those in needof treatment include those already with the disease or disorder as wellas those prone to have the disease or disorder or those in which thedisease or disorder is to be prevented.

The phrase “therapeutically effective amount” or “effective amount”means an amount of a compound of the present invention that (i) treatsor prevents the particular disease, condition, or disorder, (ii)attenuates, ameliorates, or eliminates one or more symptoms of theparticular disease, condition, or disorder, or (iii) prevents or delaysthe onset of one or more symptoms of the particular disease, condition,or disorder described herein. For cancer therapy, efficacy can, forexample, be measured by assessing the time to disease progression (TTP)and/or determining the response rate (RR).

Compounds

In one aspect the present invention provides the following compounds asdescribed herein:

-   (S)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;-   (S)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;-   (S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide;    and-   (S)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;    or a pharmaceutically acceptable thereof.

Compounds of provided herein may be prepared by any feasible syntheticroute known to one of ordinary skill in the art, for example, by theprocess illustrated in Scheme 1 below.

Pharmaceutical Compositions and Administration

In addition to one or more of the compounds provided above (orstereoisomers, geometric isomers, tautomers, solvates, metabolites,isotopes, pharmaceutically acceptable salts, or prodrugs thereof), theinvention also provides for compositions and medicaments comprising acompound of formula I or and embodiment thereof and at least onepharmaceutically acceptable carrier, diluent or excipient. Thecompositions of the invention can be used to selectively inhibit NaV1.7in patients (e.g, humans).

The term “composition,” as used herein, is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombination of the specified ingredients in the specified amounts. By“pharmaceutically acceptable” it is meant the carrier, diluent orexcipient must be compatible with the other ingredients of theformulation and not deleterious to the recipient thereof.

In one embodiment, the invention provides for pharmaceuticalcompositions (or medicaments) comprising a compound of formula I or anembodiment thereof, and its stereoisomers, geometric isomers, tautomers,solvates, metabolites, isotopes, pharmaceutically acceptable salts, orprodrugs thereof) and a pharmaceutically acceptable carrier, diluent orexcipient. In another embodiment, the invention provides for preparingcompositions (or medicaments) comprising compounds of the invention. Inanother embodiment, the invention provides for administering compoundsof formula I or its embodiments and compositions comprising compounds offormula I or an embodiment thereof to a patient (e.g., a human patient)in need thereof.

Compositions are formulated, dosed, and administered in a fashionconsistent with good medical practice. Factors for consideration in thiscontext include the particular disorder being treated, the particularmammal being treated, the clinical condition of the individual patient,the cause of the disorder, the site of delivery of the agent, the methodof administration, the scheduling of administration, and other factorsknown to medical practitioners. The effective amount of the compound tobe administered will be governed by such considerations, and is theminimum amount necessary to inhibit NaV1.7 activity as required toprevent or treat the undesired disease or disorder, such as for example,pain. For example, such amount may be below the amount that is toxic tonormal cells, or the mammal as a whole.

In one example, the therapeutically effective amount of the compound ofthe invention administered parenterally per dose will be in the range ofabout 0.01-100 mg/kg, alternatively about e.g., 0.1 to 20 mg/kg ofpatient body weight per day, with the typical initial range of compoundused being 0.3 to 15 mg/kg/day. The daily does is, in certainembodiments, given as a single daily dose or in divided doses two to sixtimes a day, or in sustained release form. In the case of a 70 kg adulthuman, the total daily dose will generally be from about 7 mg to about1,400 mg. This dosage regimen may be adjusted to provide the optimaltherapeutic response. The compounds may be administered on a regimen of1 to 4 times per day, preferably once or twice per day.

The compounds of the present invention may be administered in anyconvenient administrative form, e.g., tablets, powders, capsules,solutions, dispersions, suspensions, syrups, sprays, suppositories,gels, emulsions, patches, etc. Such compositions may contain componentsconventional in pharmaceutical preparations, e.g., diluents, carriers,pH modifiers, sweeteners, bulking agents, and further active agents.

The compounds of the invention may be administered by any suitablemeans, including oral, topical (including buccal and sublingual),rectal, vaginal, transdermal, parenteral, subcutaneous, intraperitoneal,intrapulmonary, intradermal, intrathecal and epidural and intranasal,and, if desired for local treatment, intralesional administration.Parenteral infusions include intramuscular, intravenous, intraarterial,intraperitoneal, intracerebral, intraocular, intralesional orsubcutaneous administration.

The compositions comprising compounds of formula I or an embodimentthereof are normally formulated in accordance with standardpharmaceutical practice as a pharmaceutical composition. A typicalformulation is prepared by mixing a compound of the present inventionand a diluent, carrier or excipient. Suitable diluents, carriers andexcipients are well known to those skilled in the art and are describedin detail in, e.g., Ansel, Howard C., et al., Ansel's PharmaceuticalDosage Forms and Drug Delivery Systems. Philadelphia: Lippincott,Williams & Wilkins, 2004; Gennaro, Alfonso R., et al. Remington: TheScience and Practice of Pharmacy. Philadelphia: Lippincott, Williams &Wilkins, 2000; and Rowe, Raymond C. Handbook of PharmaceuticalExcipients. Chicago, Pharmaceutical Press, 2005. The formulations mayalso include one or more buffers, stabilizing agents, surfactants,wetting agents, lubricating agents, emulsifiers, suspending agents,preservatives, antioxidants, opaquing agents, glidants, processing aids,colorants, sweeteners, perfuming agents, flavoring agents, diluents andother known additives to provide an elegant presentation of the drug(i.e., a compound of the present invention or pharmaceutical compositionthereof) or aid in the manufacturing of the pharmaceutical product(i.e., medicament).

Suitable carriers, diluents and excipients are well known to thoseskilled in the art and include materials such as carbohydrates, waxes,water soluble and/or swellable polymers, hydrophilic or hydrophobicmaterials, gelatin, oils, solvents, water and the like. The particularcarrier, diluent or excipient used will depend upon the means andpurpose for which a compound of the present invention is being applied.Solvents are generally selected based on solvents recognized by personsskilled in the art as safe (GRAS) to be administered to a mammal. Ingeneral, safe solvents are non-toxic aqueous solvents such as water andother non-toxic solvents that are soluble or miscible in water. Suitableaqueous solvents include water, ethanol, propylene glycol, polyethyleneglycols (e.g., PEG 400, PEG 300), etc. and mixtures thereof. Theformulations can also include one or more buffers, stabilizing agents,surfactants, wetting agents, lubricating agents, emulsifiers, suspendingagents, preservatives, antioxidants, opaquing agents, glidants,processing aids, colorants, sweeteners, perfuming agents, flavoringagents and other known additives to provide an elegant presentation ofthe drug (i.e., a compound of the present invention or pharmaceuticalcomposition thereof) or aid in the manufacturing of the pharmaceuticalproduct (i.e., medicament).

Acceptable diluents, carriers, excipients and stabilizers are nontoxicto recipients at the dosages and concentrations employed, and includebuffers such as phosphate, citrate and other organic acids; antioxidantsincluding ascorbic acid and methionine; preservatives (such asoctadecyldimethylbenzyl ammonium chloride; hexamethonium chloride;benzalkonium chloride, benzethonium chloride; phenol, butyl or benzylalcohol; alkyl parabens such as methyl or propyl paraben; catechol;resorcinol; cyclohexanol; 3-pentanol; and m-cresol); low molecularweight (less than about 10 residues) polypeptides; proteins, such asserum albumin, gelatin, or immunoglobulins; hydrophilic polymers such aspolyvinylpyrrolidone; amino acids such as glycine, glutamine,asparagine, histidine, arginine, or lysine; monosaccharides,disaccharides and other carbohydrates including glucose, mannose, ordextrins; chelating agents such as EDTA; sugars such as sucrose,mannitol, trehalose or sorbitol; salt-forming counter-ions such assodium; metal complexes (e.g., Zn-protein complexes); and/or non-ionicsurfactants such as TWEEN™, PLURONICS™ or polyethylene glycol (PEG). Aactive pharmaceutical ingredient of the invention (e.g., compound offormula I or an embodiment thereof) can also be entrapped inmicrocapsules prepared, for example, by coacervation techniques or byinterfacial polymerization, for example, hydroxymethylcellulose orgelatin-microcapsules and poly-(methylmethacylate) microcapsules,respectively, in colloidal drug delivery systems (for example,liposomes, albumin microspheres, microemulsions, nano-particles andnanocapsules) or in macroemulsions. Such techniques are disclosed inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philidelphia, Pa.

Sustained-release preparations of a compound of the invention (e.g.,compound of formula I or an embodiment thereof) can be prepared.Suitable examples of sustained-release preparations includesemipermeable matrices of solid hydrophobic polymers containing acompound of formula I or an embodiment thereof, which matrices are inthe form of shaped articles, e.g., films, or microcapsules. Examples ofsustained-release matrices include polyesters, hydrogels (for example,poly(2-hydroxyethyl-methacrylate), or poly(vinyl alcohol)), polylactides(U.S. Pat. No. 3,773,919), copolymers of L-glutamic acid andgamma-ethyl-L-glutamate (Sidman et al., Biopolymers 22:547, 1983),non-degradable ethylene-vinyl acetate (Langer et al., J. Biomed. Mater.Res. 15:167, 1981), degradable lactic acid-glycolic acid copolymers suchas the LUPRON DEPOT™ (injectable microspheres composed of lacticacid-glycolic acid copolymer and leuprolide acetate) andpoly-D-(−)-3-hydroxybutyric acid (EP 133,988A). Sustained releasecompositions also include liposomally entrapped compounds, which can beprepared by methods known per se (Epstein et al., Proc. Natl. Acad. Sci.U.S.A. 82:3688, 1985; Hwang et al., Proc. Natl. Acad. Sci. U.S.A.77:4030, 1980; U.S. Pat. Nos. 4,485,045 and 4,544,545; and EP 102,324A).Ordinarily, the liposomes are of the small (about 200-800 Angstroms)unilamelar type in which the lipid content is greater than about 30 mol% cholesterol, the selected proportion being adjusted for the optimaltherapy.

The formulations include those suitable for the administration routesdetailed herein. The formulations can conveniently be presented in unitdosage form and can be prepared by any of the methods well known in theart of pharmacy. Techniques and formulations generally are found inRemington: The Science and Practice of Pharmacy: Remington the Scienceand Practice of Pharmacy (2005) 21^(st) Edition, Lippincott Williams &Wilkins, Philidelphia, Pa. Such methods include the step of bringinginto association the active ingredient with the carrier whichconstitutes one or more accessory ingredients.

In general the formulations are prepared by uniformly and intimatelybringing into association the active ingredient with liquid carriers,diluents or excipients or finely divided solid carriers, diluents orexcipients, or both, and then, if necessary, shaping the product. Atypical formulation is prepared by mixing a compound of the presentinvention and a carrier, diluent or excipient. The formulations can beprepared using conventional dissolution and mixing procedures. Forexample, the bulk drug substance (i.e., compound of the presentinvention or stabilized form of the compound (e.g., complex with acyclodextrin derivative or other known complexation agent) is dissolvedin a suitable solvent in the presence of one or more of the excipientsdescribed above. A compound of the present invention is typicallyformulated into pharmaceutical dosage forms to provide an easilycontrollable dosage of the drug and to enable patient compliance withthe prescribed regimen.

In one example, compounds of formula I or an embodiment thereof may beformulated by mixing at ambient temperature at the appropriate pH, andat the desired degree of purity, with physiologically acceptablecarriers, i.e., carriers that are non-toxic to recipients at the dosagesand concentrations employed into a galenical administration form. The pHof the formulation depends mainly on the particular use and theconcentration of compound, but preferably ranges anywhere from about 3to about 8. In one example, a compound of formula I (or an embodimentthereof) is formulated in an acetate buffer, at pH 5. In anotherembodiment, the compounds of formula I or an embodiment thereof aresterile. The compound may be stored, for example, as a solid oramorphous composition, as a lyophilized formulation or as an aqueoussolution.

Formulations of a compound of the invention (e.g., compound of formula Ior an embodiment thereof) suitable for oral administration can beprepared as discrete units such as pills, capsules, cachets or tabletseach containing a predetermined amount of a compound of the invention.

Compressed tablets can be prepared by compressing in a suitable machinethe active ingredient in a free-flowing form such as a powder orgranules, optionally mixed with a binder, lubricant, inert diluent,preservative, surface active or dispersing agent. Molded tablets can bemade by molding in a suitable machine a mixture of the powdered activeingredient moistened with an inert liquid diluent. The tablets canoptionally be coated or scored and optionally are formulated so as toprovide slow or controlled release of the active ingredient therefrom.

Tablets, troches, lozenges, aqueous or oil suspensions, dispersiblepowders or granules, emulsions, hard or soft capsules, e.g., gelatincapsules, syrups or elixirs can be prepared for oral use. Formulationsof a compound of the invention (e.g., compound of formula I or anembodiment thereof) intended for oral use can be prepared according toany method known to the art for the manufacture of pharmaceuticalcompositions and such compositions can contain one or more agentsincluding sweetening agents, flavoring agents, coloring agents andpreserving agents, in order to provide a palatable preparation. Tabletscontaining the active ingredient in admixture with non-toxicpharmaceutically acceptable excipient which are suitable for manufactureof tablets are acceptable. These excipients can be, for example, inertdiluents, such as calcium or sodium carbonate, lactose, calcium orsodium phosphate; granulating and disintegrating agents, such as maizestarch, or alginic acid; binding agents, such as starch, gelatin oracacia; and lubricating agents, such as magnesium stearate, stearic acidor talc. Tablets can be uncoated or can be coated by known techniquesincluding microencapsulation to delay disintegration and adsorption inthe gastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax can be employed.

An example of a suitable oral administration form is a tablet containingabout 1 mg, 5 mg, 10 mg, 25 mg, 30 mg, 50 mg, 80 mg, 100 mg, 150 mg, 250mg, 300 mg and 500 mg of the compound of the invention compounded withabout 90-30 mg anhydrous lactose, about 5-40 mg sodium croscarmellose,about 5-30 mg polyvinylpyrrolidone (PVP) K30, and about 1-10 mgmagnesium stearate. The powdered ingredients are first mixed togetherand then mixed with a solution of the PVP. The resulting composition canbe dried, granulated, mixed with the magnesium stearate and compressedto tablet form using conventional equipment. An example of an aerosolformulation can be prepared by dissolving the compound, for example5-400 mg, of the invention in a suitable buffer solution, e.g. aphosphate buffer, adding a tonicifier, e.g. a salt such sodium chloride,if desired. The solution may be filtered, e.g., using a 0.2 micronfilter, to remove impurities and contaminants.

For treatment of the eye or other external tissues, e.g., mouth andskin, the formulations are preferably applied as a topical ointment orcream containing the active ingredient(s) in an amount of, for example,0.075 to 20% w/w. When formulated in an ointment, the active ingredientcan be employed with either a paraffinic or a water-miscible ointmentbase. Alternatively, the active ingredients can be formulated in a creamwith an oil-in-water cream base. If desired, the aqueous phase of thecream base can include a polyhydric alcohol, i.e., an alcohol having twoor more hydroxyl groups such as propylene glycol, butane 1,3-diol,mannitol, sorbitol, glycerol and polyethylene glycol (including PEG 400)and mixtures thereof. The topical formulations can desirably include acompound which enhances absorption or penetration of the activeingredient through the skin or other affected areas. Examples of suchdermal penetration enhancers include dimethyl sulfoxide and relatedanalogs.

The oily phase of the emulsions of this invention can be constitutedfrom known ingredients in a known manner. While the phase can comprisemerely an emulsifier, it desirably comprises a mixture of at least oneemulsifier with a fat or an oil or with both a fat and an oil.Preferably, a hydrophilic emulsifier is included together with alipophilic emulsifier which acts as a stabilizer. It is also preferredto include both an oil and a fat. Together, the emulsifier(s) with orwithout stabilizer(s) make up the so-called emulsifying wax, and the waxtogether with the oil and fat make up the so-called emulsifying ointmentbase which forms the oily dispersed phase of the cream formulations.Emulsifiers and emulsion stabilizers suitable for use in the formulationof the invention include Tween® 60, Span® 80, cetostearyl alcohol,benzyl alcohol, myristyl alcohol, glyceryl mono-stearate and sodiumlauryl sulfate.

In one aspect of topical applications, it is desired to administer aneffective amount of a pharmaceutical composition according to theinvention to target area, e.g., skin surfaces, mucous membranes, and thelike, which are adjacent to peripheral neurons which are to be treated.This amount will generally range from about 0.0001 mg to about 1 g of acompound of the invention per application, depending upon the area to betreated, whether the use is diagnostic, prophylactic or therapeutic, theseverity of the symptoms, and the nature of the topical vehicleemployed. A preferred topical preparation is an ointment, wherein about0.001 to about 50 mg of active ingredient is used per cc of ointmentbase. The pharmaceutical composition can be formulated as transdermalcompositions or transdermal delivery devices (“patches”). Suchcompositions include, for example, a backing, active compound reservoir,a control membrane, liner and contact adhesive. Such transdermal patchesmay be used to provide continuous pulsatile, or on demand delivery ofthe compounds of the present invention as desired.

Aqueous suspensions of a compound of the invention (e.g., compound offormula I or an embodiment thereof) contain the active materials inadmixture with excipients suitable for the manufacture of aqueoussuspensions. Such excipients include a suspending agent, such as sodiumcarboxymethylcellulose, croscarmellose, povidone, methylcellulose,hydroxypropyl methylcellulose, sodium alginate, polyvinylpyrrolidone,gum tragacanth and gum acacia, and dispersing or wetting agents such asa naturally occurring phosphatide (e.g., lecithin), a condensationproduct of an alkylene oxide with a fatty acid (e.g., polyoxyethylenestearate), a condensation product of ethylene oxide with a long chainaliphatic alcohol (e.g., heptadecaethyleneoxycetanol), a condensationproduct of ethylene oxide with a partial ester derived from a fatty acidand a hexitol anhydride (e.g., polyoxyethylene sorbitan monooleate). Theaqueous suspension can also contain one or more preservatives such asethyl or n-propyl p-hydroxybenzoate, one or more coloring agents, one ormore flavoring agents and one or more sweetening agents, such as sucroseor saccharin.

Formulations of a compound of the invention (e.g., compound of formula Ior an embodiment thereof) can be in the form of a sterile injectablepreparation, such as a sterile injectable aqueous or oleaginoussuspension. This suspension can be formulated according to the known artusing those suitable dispersing or wetting agents and suspending agentswhich have been mentioned above. The sterile injectable preparation canalso be a sterile injectable solution or suspension in a non-toxicparenterally acceptable diluent or solvent, such as a solution in1,3-butanediol or prepared as a lyophilized powder. Among the acceptablevehicles and solvents that can be employed are water, Ringer's solutionand isotonic sodium chloride solution. In addition, sterile fixed oilscan conventionally be employed as a solvent or suspending medium. Forthis purpose any bland fixed oil can be employed including syntheticmono- or diglycerides. In addition, fatty acids such as oleic acid canlikewise be used in the preparation of injectables.

The amount of active ingredient that can be combined with the carriermaterial to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration. For example, atime-release formulation intended for oral administration to humans cancontain approximately 1 to 1000 mg of active material compounded with anappropriate and convenient amount of carrier material which can varyfrom about 5 to about 95% of the total compositions (weight:weight). Thepharmaceutical composition can be prepared to provide easily measurableamounts for administration. For example, an aqueous solution intendedfor intravenous infusion can contain from about 3 to 500 g of the activeingredient per milliliter of solution in order that infusion of asuitable volume at a rate of about 30 mL/hr can occur.

Formulations suitable for parenteral administration include aqueous andnon-aqueous sterile injection solutions which can contain anti-oxidants,buffers, bacteriostats and solutes which render the formulation isotonicwith the blood of the intended recipient; and aqueous and non-aqueoussterile suspensions which can include suspending agents and thickeningagents.

Formulations suitable for topical administration to the eye also includeeye drops wherein the active ingredient is dissolved or suspended in asuitable carrier, especially an aqueous solvent for the activeingredient. The active ingredient is preferably present in suchformulations in a concentration of about 0.5 to 20% w/w, for exampleabout 0.5 to 10% w/w, for example about 1.5% w/w.

Formulations suitable for topical administration in the mouth includelozenges comprising the active ingredient in a flavored basis, usuallysucrose and acacia or tragacanth; pastilles comprising the activeingredient in an inert basis such as gelatin and glycerin, or sucroseand acacia; and mouthwashes comprising the active ingredient in asuitable liquid carrier.

Formulations for rectal administration can be presented as a suppositorywith a suitable base comprising for example cocoa butter or asalicylate.

Formulations suitable for intrapulmonary or nasal administration have aparticle size for example in the range of 0.1 to 500 microns (includingparticle sizes in a range between 0.1 and 500 microns in incrementsmicrons such as 0.5, 1, 30 microns, 35 microns, etc.), which isadministered by rapid inhalation through the nasal passage or byinhalation through the mouth so as to reach the alveolar sacs. Suitableformulations include aqueous or oily solutions of the active ingredient.Formulations suitable for aerosol or dry powder administration can beprepared according to conventional methods and can be delivered withother therapeutic agents such as compounds heretofore used in thetreatment of disorders as described below.

The formulations can be packaged in unit-dose or multi-dose containers,for example sealed ampoules and vials, and can be stored in afreeze-dried (lyophilized) condition requiring only the addition of thesterile liquid carrier, for example water, for injection immediatelyprior to use. Extemporaneous injection solutions and suspensions areprepared from sterile powders, granules and tablets of the kindpreviously described. Preferred unit dosage formulations are thosecontaining a daily dose or unit daily sub-dose, as herein above recited,or an appropriate fraction thereof, of the active ingredient.

When the binding target is located in the brain, certain embodiments ofthe invention provide for a compound of formula I (or an embodimentthereof) to traverse the blood-brain barrier. Certain neurodegenerativediseases are associated with an increase in permeability of theblood-brain barrier, such that a compound of formula I (or an embodimentthereof) can be readily introduced to the brain. When the blood-brainbarrier remains intact, several art-known approaches exist fortransporting molecules across it, including, but not limited to,physical methods, lipid-based methods, and receptor and channel-basedmethods.

Physical methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, circumventing the blood-brain barrier entirely, or bycreating openings in the blood-brain barrier.

Circumvention methods include, but are not limited to, direct injectioninto the brain (see, e.g., Papanastassiou et al., Gene Therapy9:398-406, 2002), interstitial infusion/convection-enhanced delivery(see, e.g., Bobo et al., Proc. Natl. Acad. Sci. U.S.A. 91:2076-2080,1994), and implanting a delivery device in the brain (see, e.g., Gill etal., Nature Med. 9:589-595, 2003; and Gliadel Wafers™, GuildfordPharmaceutical). Methods of creating openings in the barrier include,but are not limited to, ultrasound (see, e.g., U.S. Patent PublicationNo. 2002/0038086), osmotic pressure (e.g., by administration ofhypertonic mannitol (Neuwelt, E. A., Implication of the Blood-BrainBarrier and its Manipulation, Volumes 1 and 2, Plenum Press, N.Y.,1989)), and permeabilization by, e.g., bradykinin or permeabilizer A-7(see, e.g., U.S. Pat. Nos. 5,112,596, 5,268,164, 5,506,206, and5,686,416).

Lipid-based methods of transporting a compound of formula I (or anembodiment thereof) across the blood-brain barrier include, but are notlimited to, encapsulating the a compound of formula I (or an embodimentthereof) in liposomes that are coupled to antibody binding fragmentsthat bind to receptors on the vascular endothelium of the blood-brainbarrier (see, e.g., U.S. Patent Application Publication No.2002/0025313), and coating a compound of formula I (or an embodimentthereof) in low-density lipoprotein particles (see, e.g., U.S. PatentApplication Publication No. 2004/0204354) or apolipoprotein E (see,e.g., U.S. Patent Application Publication No. 2004/0131692).

Receptor and channel-based methods of transporting a compound of formulaI (or an embodiment thereof) across the blood-brain barrier include, butare not limited to, using glucocorticoid blockers to increasepermeability of the blood-brain barrier (see, e.g., U.S. PatentApplication Publication Nos. 2002/0065259, 2003/0162695, and2005/0124533); activating potassium channels (see, e.g., U.S. PatentApplication Publication No. 2005/0089473), inhibiting ABC drugtransporters (see, e.g., U.S. Patent Application Publication No.2003/0073713); coating a compound of formula I (or an embodimentthereof) with a transferrin and modulating activity of the one or moretransferrin receptors (see, e.g., U.S. Patent Application PublicationNo. 2003/0129186), and cationizing the antibodies (see, e.g., U.S. Pat.No. 5,004,697).

For intracerebral use, in certain embodiments, the compounds can beadministered continuously by infusion into the fluid reservoirs of theCNS, although bolus injection may be acceptable. The inhibitors can beadministered into the ventricles of the brain or otherwise introducedinto the CNS or spinal fluid. Administration can be performed by use ofan indwelling catheter and a continuous administration means such as apump, or it can be administered by implantation, e.g., intracerebralimplantation of a sustained-release vehicle. More specifically, theinhibitors can be injected through chronically implanted cannulas orchronically infused with the help of osmotic minipumps. Subcutaneouspumps are available that deliver proteins through a small tubing to thecerebral ventricles. Highly sophisticated pumps can be refilled throughthe skin and their delivery rate can be set without surgicalintervention. Examples of suitable administration protocols and deliverysystems involving a subcutaneous pump device or continuousintracerebroventricular infusion through a totally implanted drugdelivery system are those used for the administration of dopamine,dopamine agonists, and cholinergic agonists to Alzheimer's diseasepatients and animal models for Parkinson's disease, as described byHarbaugh, J. Neural Transm. Suppl. 24:271, 1987; and DeYebenes et al.,Mov. Disord. 2: 143, 1987.

A compound of formula I (or an embodiment thereof) used in the inventionare formulated, dosed, and administered in a fashion consistent withgood medical practice. Factors for consideration in this context includethe particular disorder being treated, the particular mammal beingtreated, the clinical condition of the individual patient, the cause ofthe disorder, the site of delivery of the agent, the method ofadministration, the scheduling of administration, and other factorsknown to medical practitioners. A compound of formula I (or anembodiment thereof) need not be, but is optionally formulated with oneor more agent currently used to prevent or treat the disorder inquestion. The effective amount of such other agents depends on theamount of a compound of the invention present in the formulation, thetype of disorder or treatment, and other factors discussed above.

These are generally used in the same dosages and with administrationroutes as described herein, or about from 1 to 99% of the dosagesdescribed herein, or in any dosage and by any route that isempirically/clinically determined to be appropriate.

For the prevention or treatment of disease, the appropriate dosage of acompound of formula I (or an embodiment thereof) (when used alone or incombination with other agents) will depend on the type of disease to betreated, the properties of the compound, the severity and course of thedisease, whether the compound is administered for preventive ortherapeutic purposes, previous therapy, the patient's clinical historyand response to the compound, and the discretion of the attendingphysician. The compound is suitably administered to the patient at onetime or over a series of treatments. Depending on the type and severityof the disease, about 1 g/kg to 15 mg/kg (e.g., 0.1 mg/kg-10 mg/kg) ofcompound can be an initial candidate dosage for administration to thepatient, whether, for example, by one or more separate administrations,or by continuous infusion. One typical daily dosage might range fromabout 1 g kg to 100 mg/kg or more, depending on the factors mentionedabove. For repeated administrations over several days or longer,depending on the condition, the treatment would generally be sustaineduntil a desired suppression of disease symptoms occurs. One exemplarydosage of a compound of formula I (or an embodiment thereof) would be inthe range from about 0.05 mg/kg to about 10 mg/kg. Thus, one or moredoses of about 0.5 mg/kg, 2.0 mg/kg, 4.0 mg/kg, or 10 mg/kg (or anycombination thereof) may be administered to the patient. Such doses maybe administered intermittently, e.g., every week or every three weeks(e.g., such that the patient receives from about two to about twenty,or, e.g., about six doses of the antibody). An initial higher loadingdose, followed by one or more lower doses may be administered. Anexemplary dosing regimen comprises administering an initial loading doseof about 4 mg/kg, followed by a weekly maintenance dose of about 2 mg kgof the compound. However, other dosage regimens may be useful. Theprogress of this therapy is easily monitored by conventional techniquesand assays.

Other typical daily dosages might range from, for example, about 1 g/kgto up to 100 mg/kg or more (e.g., about 1 g kg to 1 mg/kg, about 1 g/kgto about 5 mg/kg, about 1 mg kg to 10 mg/kg, about 5 mg/kg to about 200mg/kg, about 50 mg/kg to about 150 mg/mg, about 100 mg/kg to about 500mg/kg, about 100 mg/kg to about 400 mg/kg, and about 200 mg/kg to about400 mg/kg), depending on the factors mentioned above. Typically, theclinician will administer a compound until a dosage is reached thatresults in improvement in or, optimally, elimination of, one or moresymptoms of the treated disease or condition. The progress of thistherapy is easily monitored by conventional assays. One or more agentprovided herein may be administered together or at different times(e.g., one agent is administered prior to the administration of a secondagent). One or more agent may be administered to a subject usingdifferent techniques (e.g., one agent may be administered orally, whilea second agent is administered via intramuscular injection orintranasally). One or more agent may be administered such that the oneor more agent has a pharmacologic effect in a subject at the same time.Alternatively, one or more agent may be administered, such that thepharmacological activity of the first administered agent is expiredprior the administration of one or more secondarily administered agents(e.g., 1, 2, 3, or 4 secondarily administered agents).

Indications and Methods of Treatment

The compounds of the invention modulate, preferably inhibit, ion fluxthrough a voltage-dependent sodium channel in a mammal, (e.g, a human).Any such modulation, whether it be partial or complete inhibition orprevention of ion flux, is sometimes referred to herein as “blocking”and corresponding compounds as “blockers” or “inhibitors”. In general,the compounds of the invention modulate the activity of a sodium channeldownwards by inhibiting the voltage-dependent activity of the sodiumchannel, and/or reduce or prevent sodium ion flux across a cell membraneby preventing sodium channel activity such as ion flux.

Accordingly, the compounds of the invention are sodium channel blockersand are therefore useful for treating diseases and conditions inmammals, for example humans, and other organisms, including all thosediseases and conditions which are the result of aberrantvoltage-dependent sodium channel biological activity or which may beameliorated by modulation of voltage-dependent sodium channel biologicalactivity. In particular, the compounds of the invention, i.e., thecompounds of formula (I) and embodiments and (or stereoisomers,geometric isomers, tautomers, solvates, metabolites, isotopes,pharmaceutically acceptable salts, or prodrugs thereof), are useful fortreating diseases and conditions in mammals, for example humans, whichare the result of aberrant voltage-dependent NaV1.7 biological activityor which may be ameliorated by the modulation, preferably theinhibition, of NaV1.7 biological activity. In certain aspects, thecompounds of the invention selectively inhibit NaV1.7 over NaV1.5.

As defined herein, a sodium channel-mediated disease or condition refersto a disease or condition in a mammal, preferably a human, which isameliorated upon modulation of the sodium channel and includes, but isnot limited to, pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease; cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus; neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome.

In one aspect, the present invention relates to compounds,pharmaceutical compositions and methods of using the compounds andpharmaceutical compositions for the treatment of sodium channel-mediateddiseases in mammals, preferably humans and preferably diseases andconditions related to pain, central nervous conditions such as epilepsy,anxiety, depression and bipolar disease; cardiovascular conditions suchas arrhythmias, atrial fibrillation and ventricular fibrillation;neuromuscular conditions such as restless leg syndrome and muscleparalysis or tetanus; neuroprotection against stroke, neural trauma andmultiple sclerosis; and channelopathies such as erythromyalgia andfamilial rectal pain syndrome, by administering to a mammal, for examplea human, in need of such treatment an effective amount of a sodiumchannel blocker modulating, especially inhibiting, agent.

A sodium channel-mediated disease or condition also includes painassociated with HIV, HIV treatment induced neuropathy, trigeminalneuralgia, glossopharyngeal neuralgia, neuropathy secondary tometastatic infiltration, adiposis dolorosa, thalamic lesions,hypertension, autoimmune disease, asthma, drug addiction (e.g., opiate,benzodiazepine, amphetamine, cocaine, alcohol, butane inhalation),Alzheimer, dementia, age-related memory impairment, Korsakoff syndrome,restenosis, urinary dysfunction, incontinence, Parkinson's disease,cerebrovascular ischemia, neurosis, gastrointestinal disease, sicklecell anemia, transplant rejection, heart failure, myocardial infarction,reperfusion injury, intermittant claudication, angina, convulsion,respiratory disorders, cerebral or myocardial ischemias, long-QTsyndrome, Catecholeminergic polymorphic ventricular tachycardia,ophthalmic diseases, spasticity, spastic paraplegia, myopathies,myasthenia gravis, paramyotonia congentia, hyperkalemic periodicparalysis, hypokalemic periodic paralysis, alopecia, anxiety disorders,psychotic disorders, mania, paranoia, seasonal affective disorder, panicdisorder, obsessive compulsive disorder (OCD), phobias, autism,Aspergers Syndrome, Retts syndrome, disintegrative disorder, attentiondeficit disorder, aggressivity, impulse control disorders, thrombosis,pre clampsia, congestive cardiac failure, cardiac arrest, Freidrich'sataxia, Spinocerebellear ataxia, myelopathy, radiculopathy, systemiclupus erythamatosis, granulomatous disease, olivo-ponto-cerebellaratrophy, spinocerebellar ataxia, episodic ataxia, myokymia, progressivepallidal atrophy, progressive supranuclear palsy and spasticity,traumatic brain injury, cerebral oedema, hydrocephalus injury, spinalcord injury, anorexia nervosa, bulimia, Prader-Willi syndrome, obesity,optic neuritis, cataract, retinal haemorrhage, ischaemic retinopathy,retinitis pigmentosa, acute and chronic glaucoma, macular degeneration,retinal artery occlusion, Chorea, Huntington's chorea, cerebral edema,proctitis, post-herpetic neuralgia, eudynia, heat sensitivity,sarcoidosis, irritable bowel syndrome, Tourette syndrome, Lesch-NyhanSyndrome, Brugado syndrome, Liddle syndrome, Crohns disease, multiplesclerosis and the pain associated with multiple sclerosis (MS),amyotrophic lateral sclerosis (ALS), disseminated sclerosis, diabeticneuropathy, peripheral neuropathy, charcot marie tooth syndrome,arthritic, rheumatoid arthritis, osteoarthritis, chondrocalcinosis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,myotonic dystrophy, muscular dystrophy, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, mental handicap,hypothyroidism, bipolar depression, anxiety, schizophrenia, sodiumchannel toxin related illnesses, familial erythromelalgia, primaryerythromelalgia, rectal pain, cancer, epilepsy, partial and generaltonic seizures, febrile seizures, absence seizures (petit mal),myoclonic seizures, atonic seizures, clonic seizures, Lennox Gastaut,West Syndome (infantile spasms), multiresistant seizures, seizureprophylaxis (anti-epileptogenic), familial Mediterranean fever syndrome,gout, restless leg syndrome, arrhythmias, fibromyalgia, neuroprotectionunder ischaemic conditions caused by stroke or neural trauma,tachy-arrhythmias, atrial fibrillation and ventricular fibrillation andas a general or local anaesthetic.

As used herein, the term “pain” refers to all categories of pain and isrecognized to include, but is not limited to, neuropathic pain,inflammatory pain, nociceptive pain, idiopathic pain, neuralgic pain,orofacial pain, burn pain, burning mouth syndrome, somatic pain,visceral pain, myofacial pain, dental pain, cancer pain, chemotherapypain, trauma pain, surgical pain, post-surgical pain, childbirth pain,labor pain, chronic regional pain syndrome (CRPS), reflex sympatheticdystrophy, brachial plexus avulsion, neurogenic bladder, acute pain(e.g., musculoskeletal and post-operative pain), chronic pain,persistent pain, peripherally mediated pain, centrally mediated pain,chronic headache, migraine headache, familial hemiplegic migraine,conditions associated with cephalic pain, sinus headache, tensionheadache, phantom limb pain, peripheral nerve injury, pain followingstroke, thalamic lesions, radiculopathy, HIV pain, post-herpetic pain,non-cardiac chest pain, irritable bowel syndrome and pain associatedwith bowel disorders and dyspepsia, and combinations thereof.

Furthermore, sodium channel blockers have clinical uses in addition topain. The present invention therefore also relates to compounds,pharmaceutical compositions and methods of using the compounds andpharmaceutical compositions for the treatment of diseases or conditionssuch as cancer and pruritus (itch).

Pruritus, commonly known as itch, is a common dermatological condition.While the exact causes of pruritus are complex and incompletelyunderstood, there has long been evidence that itch involves sensoryneurons, especially C fibers, similar to those that mediate pain(Schmelz, M., et al., J. Neurosci. (1997), 17: 8003-8). In particular,it is believed that sodium influx through voltage-gated sodium channelsis essential for the propagation of itch sensation from the skin.Transmission of the itch impulses results in the unpleasant sensationthat elicits the desire or reflex to scratch.

Multiple causes and electrical pathways for eliciting itch are known. Inhumans, pruritus can be elicited by histamine or PAR-2 agonists such asmucunain that activate distinct populations of C fibers (Namer, B., etal., J. Neurophysiol. (2008), 100: 2062-9). A variety of neurotrophicpeptides are known to mediate itch in animal models (Wang, H., andYosipovitch, G., International Journal of Dermatology (2010), 49: 1-11).Itch can also be elicited by opioids, evidence of distinct pharmacologyfrom that of pain responses.

There exists a complex interaction between itch and pain responses thatarises in part from the overlapping sensory input from the skin (Ikoma,A., et al., Arch. Dermatol. (2003), 139: 1475-8) and also from thediverse etiology of both pain and pruritus. Pain responses canexacerbate itching by enhancing central sensitization or lead toinhibition of painful scratching. Particularly severe forms of chronicitch occur when pain responses are absent, as in the case ofpost-herpetic itch (Oaklander, A. L., et al., Pain (2002), 96: 9-12).

The compounds of the invention can also be useful for treating pruritus.The rationale for treating itch with inhibitors of voltage-gated sodiumchannels, especially NaV1.7, is as follows:

The propagation of electrical activity in the C fibers that sensepruritinergic stimulants requires sodium entry through voltage-gatedsodium channels.

NaV1.7 is expressed in the C fibers and kerotinocytes in human skin(Zhao, P., et al., Pain (2008), 139: 90-105).

A gain of function mutation of NaV1.7 (L858F) that causeserythromelalgia also causes chronic itch (Li, Y., et al., Clinical andExperimental Dermatology (2009), 34: e313-e4).

Chronic itch can be alleviated with treatment by sodium channelblockers, such as the local anesthetic lidocaine (Oaklander, A. L., etal., Pain (2002), 96: 9-12; Villamil, A. G., et al., The AmericanJournal of Medicine (2005), 118: 1160-3). In these reports, lidocainewas effective when administered either intravenously or topically (aLidoderm patch). Lidocaine can have multiple activities at the plasmaconcentrations achieved when administered systemically, but whenadministered topically, the plasma concentrations are only about 1 μM(Center for Drug Evaluation and Research NDA 20-612). At theseconcentrations, lidocaine is selective for sodium channel block andinhibits spontaneous electrical activity in C fibers and pain responsesin animal models (Xiao, W. H., and Bennett, G. J. Pain (2008), 137:218-28). The types of itch or skin irritation, include, but are notlimited to:

psoriatic pruritus, itch due to hemodyalisis, aguagenic pruritus, anditching caused by skin disorders (e.g., contact dermatitis), systemicdisorders, neuropathy, psychogenic factors or a mixture thereof;

itch caused by allergic reactions, insect bites, hypersensitivity (e.g.,dry skin, acne, eczema, psoriasis), inflammatory conditions or injury;

itch associated with vulvar vestibulitis; and

skin irritation or inflammatory effect from administration of anothertherapeutic such as, for example, antibiotics, antivirals andantihistamines.

The compounds of the invention are also useful in treating certaincancers, such as hormone sensitive cancers, such as prostate cancer(adenocarcinoma), breast cancer, ovarian cancer, testicular cancer andthyroid neoplasia, in a mammal, preferably a human. The voltage gatedsodium channels have been demonstrated to be expressed in prostate andbreast cancer cells. Up-regulation of neonatal NaV1.5 occurs as anintegral part of the metastatic process in human breast cancer and couldserve both as a novel marker of the metastatic phenotype and atherapeutic target (Clin. Cancer Res. (2005), Aug. 1; 11(15): 5381-9).Functional expression of voltage-gated sodium channel alpha-subunits,specifically NaV1.7, is associated with strong metastatic potential inprostate cancer (CaP) in vitro. Voltage-gated sodium channelalpha-subunits immunostaining, using antibodies specific to the sodiumchannel alpha subunit was evident in prostatic tissues and markedlystronger in CaP vs non-CaP patients (Prostate Cancer Prostatic Dis.,2005; 8(3):266-73). See also Diss, J. K. J., et al., Mol. Cell.Neurosci. (2008), 37:537-547 and Kis-Toth, K., et al., The Journal ofImmunology (2011), 187:1273-1280.

In consideration of the above, in one embodiment, the present inventionprovides a method for treating a mammal for, or protecting a mammal fromdeveloping, a sodium channel-mediated disease, especially pain,comprising administering to the mammal, especially a human, atherapeutically effective amount of a compound of the invention or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention wherein the compound modulates theactivity of one or more voltage-dependent sodium channels.

In another embodiment of the invention is a method of treating a diseaseor a condition in a mammal, preferably a human, wherein the disease orcondition is selected from the group consisting of pain, depression,cardiovascular diseases, respiratory diseases, and psychiatric diseases,and combinations thereof, and wherein the method comprises administeringto the mammal a therapeutically effective amount of an embodiment of acompound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

One embodiment of this embodiment is wherein the disease or condition isselected from the group consisting of acute pain, chronic pain,neuropathic pain, inflammatory pain, visceral pain, cancer pain,chemotherapy pain, trauma pain, surgical pain, post surgical pain,childbirth pain, labor pain, neurogenic bladder, ulcerative colitis,persistent pain, peripherally mediated pain, centrally mediated pain,chronic headache, migraine headache, sinus headache, tension headache,phantom limb pain, peripheral nerve injury, and combinations thereof.

Another embodiment of this embodiment is wherein the disease orcondition is selected from the group consisting of pain associated withHIV, HIV treatment induced neuropathy, trigeminal neuralgia, postherpetic neuralgia, eudynia, heat sensitivity, tosarcoidosis, irritablebowel syndrome, Crohns disease, pain associated with multiple sclerosis(MS), amyotrophic lateral sclerosis (ALS), diabetic neuropathy,peripheral neuropathy, arthritic, rheumatoid arthritis, osteoarthritis,atherosclerosis, paroxysmal dystonia, myasthenia syndromes, myotonia,malignant hyperthermia, cystic fibrosis, pseudoaldosteronism,rhabdomyolysis, hypothyroidism, bipolar depression, anxiety,schizophrenia, sodium channel toxin related illnesses, familialerythromelalgia, primary erythromelalgia, familial rectal pain, cancer,epilepsy, partial and general tonic seizures, restless leg syndrome,arrhythmias, fibromyalgia, neuroprotection under ischaemic conditionscaused by stroke or neural trauma, tachy arrhythmias, atrialfibrillation and ventricular fibrillation.

Another embodiment of the invention is a method of treating, but notpreventing, pain in a mammal, wherein the method comprises administeringto the mammal a therapeutically effective amount of a compound of theinvention, as set forth above, as a stereoisomer, enantiomer or tautomerthereof or mixtures thereof, or a pharmaceutically acceptable salt,solvate or prodrug thereof, or a pharmaceutical composition comprising atherapeutically effective amount of a compound of the invention, as setforth above, as a stereoisomer, enantiomer or tautomer thereof ormixtures thereof, or a pharmaceutically acceptable salt, solvate orprodrug thereof, and a pharmaceutically acceptable excipient.

One embodiment of this embodiment is a method wherein the pain isselected from the group consisting of neuropathic pain, inflammatorypain, visceral pain, cancer pain, chemotherapy pain, trauma pain,surgical pain, post surgical pain, childbirth pain, labor pain, dentalpain, chronic pain, persistent pain, peripherally mediated pain,centrally mediated pain, chronic headache, migraine headache, sinusheadache, tension headache, phantom limb pain, peripheral nerve injury,trigeminal neuralgia, post herpetic neuralgia, eudynia, familialerythromelalgia, primary erythromelalgia, familial rectal pain orfibromyalgia, and combinations thereof.

Another embodiment of this embodiment is a method wherein the pain isassociated with a disease or condition selected from HIV, HIV treatmentinduced neuropathy, heat sensitivity, tosarcoidosis, irritable bowelsyndrome, Crohns disease, multiple sclerosis, amyotrophic lateralsclerosis, diabetic neuropathy, peripheral neuropathy, rheumatoidarthritis, osteoarthritis, atherosclerosis, paroxysmal dystonia,myasthenia syndromes, myotonia, malignant hyperthermia, cystic fibrosis,pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolar depression,anxiety, schizophrenia, sodium channel toxin related illnesses,neurogenic bladder, ulcerative colitis, cancer, epilepsy, partial andgeneral tonic seizures, restless leg syndrome, arrhythmias, ischaemicconditions caused by stroke or neural trauma, tachy arrhythmias, atrialfibrillation and ventricular fibrillation.

Another embodiment of the invention is the method of treating pain in amammal, preferably a human, by the inhibition of ion flux through avoltage dependent sodium channel in the mammal, wherein the methodcomprises administering to the mammal a therapeutically effective amountof an embodiment of a compound of the invention, as set forth above, asa stereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating pruritusin a mammal, preferably a human, wherein the method comprisesadministering to the mammal a therapeutically effective amount of anembodiment of a compound of the invention, as set forth above, as astereoisomer, enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of treating cancer ina mammal, preferably a human, wherein the method comprises administeringto the mammal a therapeutically effective amount of an embodiment of acompound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, or apharmaceutical composition comprising a therapeutically effective amountof a compound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof, and apharmaceutically acceptable excipient.

Another embodiment of the invention is the method of decreasing ion fluxthrough a voltage dependent sodium channel in a cell in a mammal,wherein the method comprises contacting the cell with an embodiment of acompound of the invention, as set forth above, as a stereoisomer,enantiomer or tautomer thereof or mixtures thereof, or apharmaceutically acceptable salt, solvate or prodrug thereof.

Another embodiment of the invention is the method of selectivelyinhibiting a first voltage-gated sodium channel over a secondvoltage-gated sodium channel in a mammal, wherein the method comprisesadministering to the mammal an inhibitory amount of a compound offormula (I), or an embodiment of a compound of formula (I).

Another embodiment of the invention is the method of selectivelyinhibiting NaV1.7 in a mammal or a mammalian cell as compared to NaV1.5,wherein the method comprises administering to the mammal an inhibitoryamount of a compound of formula (I) or an embodiment of an embodimentthereof.

For each of the above embodiments described related to treating diseasesand conditions in a mammal, the present invention also contemplatesrelatedly a compound of formula I or an embodiment thereof for the useas a medicament in the treatment of such diseases and conditions.

For each of the above embodiments described related to treating diseasesand conditions in a mammal, the present invention also contemplatesrelatedly the use of a compound of formula I or an embodiment thereoffor the manufacture of a medicament for the treatment of such diseasesand conditions.

Another embodiment of the invention is a method of using the compoundsof formula (I) as standards or controls in in vitro or in vivo assays indetermining the efficacy of test compounds in modulatingvoltage-dependent sodium channels.

In another embodiment of the invention, the compounds of formula (I) areisotopically-labeled by having one or more atoms therein replaced by anatom having a different atomic mass or mass number. Suchisotopically-labeled (i.e., radiolabelled) compounds of formula (I) areconsidered to be within the scope of this invention. Examples ofisotopes that can be incorporated into the compounds of formula (I)include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous,sulfur, fluorine, chlorine, and iodine, such as, but not limited to, ²H,³H, ¹¹C, ¹³C, ¹⁴C, ¹³N, ¹⁵N, ¹⁵O, ¹⁷O, ¹⁸O, ³¹P, ³²p, ³⁵S, ¹⁸F, ³⁶Cl,¹²³I, and ¹²⁵I, respectively. These isotopically-labeled compounds wouldbe useful to help determine or measure the effectiveness of thecompounds, by characterizing, for example, the site or mode of action onthe sodium channels, or binding affinity to pharmacologically importantsite of action on the sodium channels, particularly NaV1.7. Certainisotopically-labeled compounds of formula (I), for example, thoseincorporating a radioactive isotope, are useful in drug and/or substratetissue distribution studies. The radioactive isotopes tritium, i.e. ³H,and carbon-14, i.e., ¹⁴C, are particularly useful for this purpose inview of their ease of incorporation and ready means of detection.

Substitution with heavier isotopes such as deuterium, i.e. ²H, mayafford certain therapeutic advantages resulting from greater metabolicstability, for example, increased in vivo half-life or reduced dosagerequirements, and hence may be preferred in some circumstances.

Substitution with positron emitting isotopes, such as ¹¹C, ¹⁸F, ¹⁵O and¹³N, can be useful in Positron Emission Topography (PET) studies forexamining substrate receptor occupancy. Isotopically-labeled compoundsof formula (I) can generally be prepared by conventional techniquesknown to those skilled in the art or by processes analogous to thosedescribed in the Examples as set out below using an appropriateisotopically-labeled reagent in place of the non-labeled reagentpreviously employed.

Testing Compounds

The assessment of the compounds of the invention in mediating,especially inhibiting, the sodium channel ion flux can be determinedusing the assays described hereinbelow. Alternatively, the assessment ofthe compounds in treating conditions and diseases in humans may beestablished in industry standard animal models for demonstrating theefficacy of compounds in treating pain. Animal models of humanneuropathic pain conditions have been developed that result inreproducible sensory deficits (allodynia, hyperalgesia, and spontaneouspain) over a sustained period of time that can be evaluated by sensorytesting. By establishing the degree of mechanical, chemical, andtemperature induced allodynia and hyperalgesia present, severalphysiopathological conditions observed in humans can be modeled allowingthe evaluation of pharmacotherapies.

In rat models of peripheral nerve injury, ectopic activity in theinjured nerve corresponds to the behavioural signs of pain. In thesemodels, intravenous application of the sodium channel blocker and localanesthetic lidocaine can suppress the ectopic activity and reverse thetactile allodynia at concentrations that do not affect general behaviourand motor function (Mao, J. and Chen, L. L, Pain (2000), 87:7-17).Allometric scaling of the doses effective in these rat models,translates into doses similar to those shown to be efficacious in humans(Tanelian, D. L. and Brose, W. G., Anesthesiology (1991),74(5):949-951). Furthermore, Lidoderm, lidocaine applied in the form ofa dermal patch, is currently an FDA approved treatment for post-herpeticneuralgia (Devers, A. and Glaler, B. S., Clin. J. Pain (2000),16(3):205-8).

The present invention readily affords many different means foridentification of sodium channel modulating agents that are useful astherapeutic agents. Identification of modulators of sodium channel canbe assessed using a variety of in vitro and in vivo assays, e.g.,measuring current, measuring membrane potential, measuring ion flux,(e.g., sodium or guanidinium), measuring sodium concentration, measuringsecond messengers and transcription levels, and using e.g.,voltage-sensitive dyes, radioactive tracers, and patch-clampelectrophysiology.

One such protocol involves the screening of chemical agents for abilityto modulate the activity of a sodium channel thereby identifying it as amodulating agent.

A typical assay described in Bean et al., J. General Physiology (1983),83:613-642, and Leuwer, M., et al., Br. J. Pharmacol (2004),141(1):47-54, uses patch-clamp techniques to study the behaviour ofchannels. Such techniques are known to those skilled in the art, and maybe developed, using current technologies, into low or medium throughputassays for evaluating compounds for their ability to modulate sodiumchannel behaviour.

Throughput of test compounds is an important consideration in the choiceof screening assay to be used. In some strategies, where hundreds ofthousands of compounds are to be tested, it is not desirable to use lowthroughput means. In other cases, however, low throughput issatisfactory to identify important differences between a limited numberof compounds. Often it will be necessary to combine assay types toidentify specific sodium channel modulating compounds.

Electrophysiological assays using patch clamp techniques is accepted asa gold standard for detailed characterization of sodium channel compoundinteractions, and as described in Bean et al., op. cit. and Leuwer, M.,et al., op. cit. There is a manual low-throughput screening (LTS) methodwhich can compare 2-10 compounds per day; a recently developed systemfor automated medium-throughput screening (MTS) at 20-50 patches (i.e.compounds) per day; and a technology from Molecular Devices Corporation(Sunnyvale, Calif.) which permits automated high-throughput screening(HTS) at 1000-3000 patches (i.e. compounds) per day.

One automated patch-clamp system utilizes planar electrode technology toaccelerate the rate of drug discovery. Planar electrodes are capable ofachieving high-resistance, cells-attached seals followed by stable,low-noise whole-cell recordings that are comparable to conventionalrecordings. A suitable instrument is the PatchXpress 7000A (AxonInstruments Inc, Union City, Calif.). A variety of cell lines andculture techniques, which include adherent cells as well as cellsgrowing spontaneously in suspension are ranked for seal success rate andstability. Immortalized cells (e.g. HEK and CHO) stably expressing highlevels of the relevant sodium ion channel can be adapted intohigh-density suspension cultures.

Other assays can be selected which allow the investigator to identifycompounds which block specific states of the channel, such as the openstate, closed state or the resting state, or which block transition fromopen to closed, closed to resting or resting to open. Those skilled inthe art are generally familiar with such assays.

Binding assays are also available. Designs include traditionalradioactive filter based binding assays or the confocal basedfluorescent system available from Evotec OAI group of companies(Hamburg, Germany), both of which are HTS.

Radioactive flux assays can also be used. In this assay, channels arestimulated to open with veratridine or aconitine and held in astabilized open state with a toxin, and channel blockers are identifiedby their ability to prevent ion influx. The assay can use radioactive22[Na] and 14[C] guanidinium ions as tracers. FlashPlate & Cytostar-Tplates in living cells avoids separation steps and are suitable for HTS.Scintillation plate technology has also advanced this method to HTSsuitability. Because of the functional aspects of the assay, theinformation content is reasonably good.

Yet another format measures the redistribution of membrane potentialusing the FLIPR system membrane potential kit (HTS) available fromMolecular Dynamics (a division of Amersham Biosciences, Piscataway,N.J.). This method is limited to slow membrane potential changes. Someproblems may result from the fluorescent background of compounds. Testcompounds may also directly influence the fluidity of the cell membraneand lead to an increase in intracellular dye concentrations. Still,because of the functional aspects of the assay, the information contentis reasonably good.

Sodium dyes can be used to measure the rate or amount of sodium ioninflux through a channel. This type of assay provides a very highinformation content regarding potential channel blockers. The assay isfunctional and would measure Na+ influx directly. CoroNa Red, SBFIand/or sodium green (Molecular Probes, Inc. Eugene Oreg.) can be used tomeasure Na influx; all are Na responsive dyes. They can be used incombination with the FLIPR instrument. The use of these dyes in a screenhas not been previously described in the literature. Calcium dyes mayalso have potential in this format.

In another assay, FRET based voltage sensors are used to measure theability of a test compound to directly block Na influx. Commerciallyavailable HTS systems include the VIPR™ II FRET system (LifeTechnologies, or Aurora Biosciences Corporation, San Diego, Calif., adivision of Vertex Pharmaceuticals, Inc.) which may be used inconjunction with FRET dyes, also available from Aurora Biosciences. Thisassay measures sub-second responses to voltage changes. There is norequirement for a modifier of channel function. The assay measuresdepolarization and hyperpolarizations, and provides ratiometric outputsfor quantification. A somewhat less expensive MTS version of this assayemploys the FLEXstation™ (Molecular Devices Corporation) in conjunctionwith FRET dyes from Aurora Biosciences. Other methods of testing thecompounds disclosed herein are also readily known and available to thoseskilled in the art.

Modulating agents so identified are then tested in a variety of in vivomodels so as to determine if they alleviate pain, especially chronicpain or other conditions such as cancer and pruritus (itch) with minimaladverse events. The assays described below in the Biological AssaysSection are useful in assessing the biological activity of the instantcompounds.

Typically, the efficacy of a compound of the invention is expressed byits IC50 value (“Inhibitory Concentration—50%”), which is the measure ofthe amount of compound required to achieve 50% inhibition of theactivity of the target sodium channel over a specific time period. Forexample, representative compounds of the present invention havedemonstrated IC50's ranging from less than 100 nanomolar to less than 10micromolar in the patch voltage clamp NaV1.7 electrophysiology assaydescribed herein.

In another aspect of the invention, the compounds of the invention canbe used in in vitro or in vivo studies as exemplary agents forcomparative purposes to find other compounds also useful in treatmentof, or protection from, the various diseases disclosed herein.

Another aspect of the invention relates to inhibiting NaV1.1, NaV1.2,NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7, NaV1.8, or NaV1.9 activity,preferably NaV1.7 activity, in a biological sample or a mammal,preferably a human, which method comprises administering to the mammal,preferably a human, or contacting said biological sample with a compoundof formula (I) or a pharmaceutical composition comprising a compound offormula (I). The term “biological sample”, as used herein, includes,without limitation, cell cultures or extracts thereof, biopsied materialobtained from a mammal or extracts thereof, and blood, saliva, urine,feces, semen, tears, or other body fluids or extracts thereof.

Inhibition of NaV1.1, NaV1.2, NaV1.3, NaV1.4, NaV1.5, NaV1.6, NaV1.7,NaV1.8, or NaV1.9 activity in a biological sample is useful for avariety of purposes that are known to one of skill in the art. Examplesof such purposes include, but are not limited to, the study of sodiumion channels in biological and pathological phenomena; and thecomparative evaluation of new sodium ion channel inhibitors.

The compounds of the invention (or stereoisomers, geometric isomers,tautomers, solvates, metabolites, isotopes, pharmaceutically acceptablesalts, or prodrugs thereof) and/or the pharmaceutical compositionsdescribed herein which comprise a pharmaceutically acceptable excipientand one or more compounds of the invention, can be used in thepreparation of a medicament for the treatment of sodium channel-mediateddisease or condition in a mammal.

Combination Therapy

The compounds of the invention may be usefully combined with one or moreother compounds of the invention or one or more other therapeutic agentor as any combination thereof, in the treatment of sodiumchannel-mediated diseases and conditions. For example, a compound of theinvention may be administered simultaneously, sequentially or separatelyin combination with other therapeutic agents, including, but not limitedto:

opiates analgesics, e.g., morphine, heroin, cocaine, oxymorphine,levorphanol, levallorphan, oxycodone, codeine, dihydrocodeine,propoxyphene, nalmefene, fentanyl, hydrocodone, hydromorphone,meripidine, methadone, nalorphine, naloxone, naltrexone, buprenorphine,butorphanol, nalbuphine and pentazocine;

non-opiate analgesics, e.g., acetomeniphen, salicylates (e.g., aspirin);

nonsteroidal antiinflammatory drugs (NSAIDs), e.g., ibuprofen, naproxen,fenoprofen, ketoprofen, celecoxib, diclofenac, diflusinal, etodolac,fenbufen, fenoprofen, flufenisal, flurbiprofen, ibuprofen, indomethacin,ketoprofen, ketorolac, meclofenamic acid, mefenamic acid, meloxicam,nabumetone, naproxen, nimesulide, nitroflurbiprofen, olsalazine,oxaprozin, phenylbutazone, piroxicam, sulfasalazine, sulindac, tolmetinand zomepirac;

anticonvulsants, e.g., carbamazepine, oxcarbazepine, lamotrigine,valproate, topiramate, gabapentin and pregabalin;

antidepressants such as tricyclic antidepressants, e.g., amitriptyline,clomipramine, despramine, imipramine and nortriptyline;

COX-2 selective inhibitors, e.g., celecoxib, rofecoxib, parecoxib,valdecoxib, deracoxib, etoricoxib, and lumiracoxib;

alpha-adrenergics, e.g., doxazosin, tamsulosin, clonidine, guanfacine,dexmetatomidine, modafinil, and 4-amino-6,7-dimethoxy-2-(5-methanesulfonamido-1,2,3,4-tetrahydroisoquinol-2-yl)-5-(2-pyridyl) quinazoline;

barbiturate sedatives, e.g., amobarbital, aprobarbital, butabarbital,butabital, mephobarbital, metharbital, methohexital, pentobarbital,phenobartital, secobarbital, talbutal, theamylal and thiopental;

tachykinin (NK) antagonist, particularly an NK-3, NK-2 or NK-1antagonist, e.g., (αR,9R)-7-[3,5-bis(trifluoromethyl)benzyl)]-8,9,10,11-tetrahydro-9-methyl-5-(4-methylphenyl)-7H-[1,4]diazocino[2,1-g][1,7]-naphthyridine-6-13-dione(TAK-637),5-[[2R,3S)-2-[(1R)-1-[3,5-bis(trifluoromethylphenyl]ethoxy-3-(4-fluorophenyl)-4-morpholinyl]-methyl]-1,2-dihydro-3H-1,2,4-triazol-3-one(MK-869), aprepitant, lanepitant, dapitant or3-[[2-methoxy5-(trifluoromethoxy)phenyl]-methylamino]-2-phenylpiperidine(2S,3S);

coal-tar analgesics, in particular paracetamol;

serotonin reuptake inhibitors, e.g., paroxetine, sertraline,norfluoxetine (fluoxetine desmethyl metabolite), metabolitedemethylsertraline, ′3 fluvoxamine, paroxetine, citalopram, citaloprammetabolite desmethylcitalopram, escitalopram, d,l-fenfluramine,femoxetine, ifoxetine, cyanodothiepin, litoxetine, dapoxetine,nefazodone, cericlamine, trazodone and fluoxetine;

noradrenaline (norepinephrine) reuptake inhibitors, e.g., maprotiline,lofepramine, mirtazepine, oxaprotiline, fezolamine, tomoxetine,mianserin, buproprion, buproprion metabolite hydroxybuproprion,nomifensine and viloxazine (Vivalan®)), especially a selectivenoradrenaline reuptake inhibitor such as reboxetine, in particular(S,S)-reboxetine, and venlafaxine duloxetine neurolepticssedative/anxiolytics;

dual serotonin-noradrenaline reuptake inhibitors, such as venlafaxine,venlafaxine metabolite O-desmethylvenlafaxine, clomipramine,clomipramine metabolite desmethylclomipramine, duloxetine, milnacipranand imipramine;

acetylcholinesterase inhibitors such as donepezil;

5-HT3 antagonists such as ondansetron;

metabotropic glutamate receptor (mGluR) antagonists;

local anaesthetic such as mexiletine and lidocaine;

corticosteroid such as dexamethasone;

antiarrhythimics, e.g., mexiletine and phenytoin;

muscarinic antagonists, e.g., tolterodine, propiverine, tropsium tchloride, darifenacin, solifenacin, temiverine and ipratropium;

cannabinoids;

vanilloid receptor agonists (e.g., resinferatoxin) or antagonists (e.g.,capsazepine);

sedatives, e.g., glutethimide, meprobamate, methaqualone, anddichloralphenazone;

anxiolytics such as benzodiazepines,

antidepressants such as mirtazapine,

topical agents (e.g., lidocaine, capsacin and resiniferotoxin);

muscle relaxants such as benzodiazepines, baclofen, carisoprodol,chlorzoxazone, cyclobenzaprine, methocarbamol and orphrenadine;

anti-histamines or H1 antagonists;

NMDA receptor antagonists;

5-HT receptor agonists/antagonists;

PDEV inhibitors;

Tramadol®;

cholinergic (nicotinc) analgesics;

alpha-2-delta ligands;

prostaglandin E2 subtype antagonists;

leukotriene B4 antagonists;

5-lipoxygenase inhibitors; and

5-HT3 antagonists.

Sodium channel-mediated diseases and conditions that may be treatedand/or prevented using such combinations include but not limited to,pain, central and peripherally mediated, acute, chronic, neuropathic aswell as other diseases with associated pain and other central nervousdisorders such as epilepsy, anxiety, depression and bipolar disease; orcardiovascular disorders such as arrhythmias, atrial fibrillation andventricular fibrillation; neuromuscular disorders such as restless legsyndrome and muscle paralysis or tetanus; neuroprotection againststroke, neural trauma and multiple sclerosis; and channelopathies suchas erythromyalgia and familial rectal pain syndrome.

As used herein “combination” refers to any mixture or permutation of oneor more compounds of the invention and one or more other compounds ofthe invention or one or more additional therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include simultaneous orsequentially delivery of a compound of the invention with one or moretherapeutic agents. Unless the context makes clear otherwise,“combination” may include dosage forms of a compound of the inventionwith another therapeutic agent. Unless the context makes clearotherwise, “combination” may include routes of administration of acompound of the invention with another therapeutic agent. Unless thecontext makes clear otherwise, “combination” may include formulations ofa compound of the invention with another therapeutic agent. Dosageforms, routes of administration and pharmaceutical compositions include,but are not limited to, those described herein.

The invention will be more fully understood by reference to thefollowing examples. They should not, however, be construed as limitingthe scope of the invention.

EXAMPLES

These examples serve to provide guidance to a skilled artisan to prepareand use the compounds, compositions and methods of the invention. Whileparticular embodiments of the present invention are described, theskilled artisan will appreciate that various changes and modificationscan be made without departing from the spirit and scope of theinventions.

The chemical reactions in the examples described can be readily adaptedto prepare a number of other compounds of the invention, and alternativemethods for preparing the compounds of this invention are deemed to bewithin the scope of this invention. For example, the synthesis ofnon-examplified compounds according to the invention can be successfullyperformed by modifications apparent to those skilled in the art, forexample, by appropriately protecting interferring group, by utilizingother suitable reagents known in the art, for example, by appropriatelyprotecting interferring groups by utilizing other suitable reagentsknown in the art other than those described, and/or by making routinemodifications of reaction conditions.

In the examples below, unless otherwise indicated all temperatures areset forth in degrees Celcius. Commerically aviable reagents werepurchased from suppliers such as Aldrich Chemical Company, Lancaster,TCI or Maybridge and were used without further purification unlessotherwise indicated. The reactions set forth below were done generallyunder a positive pressure of nitrogen or argon or with a drying tube(unless otherwise stated) in anhydrous solvents, and the reaction flaskswere typically fitted with rubber septa for the introduction ofsubstrates and reagents via syringe. Glassware was oven dried and/orheat dried. ¹H NMR spectra were obtained in deuterated CDCl₃, d₆-DMSO,CH₃OD or d₆-acetone solvent solutions (reported in ppm) using ortrimethylsilane (TMS) or residual non-deuterated solvent peaks as thereference standard. When peak multiplicities are reported, the followingabbreviates are used: s (singlet), d (doublet), t (triplet), q(quartet), m (multiplet, br (broadened), dd (doublet of doublets), dt(doublet of triplets). Coupling constants, when given, ar reported in Hz(Hertz).

All abbreviations used to describe reagents, reaction conditions orequipment are intended to be consistent with the definitions set forthin the “List of standard abbreviates and acronyms”. The chemical namesof discrete compounds of the invention were obtained using the structurenaming feature of ChemDraw naming program.

LCMS Analytical Methods

Final compounds were analyzed using three different LC/MS conditions,with UV detector monitoring at 214 nm and 254 nm, and mass spectrometryscanning 110-800 amu in ESI+ ionization mode.

LC/MS Method A: (8.0 min LC-MS Run): XBridge C18 column (4.6×50 mm, 3.5μm, 40° C.); mobile phase: A=10 mM ammonium hydrogen carbonate in water,B=acetonitrile; gradient: 0.0-8.0 min, 5%-95% B; flow rate=1.2 mL/min.

LC/MS Method B: (8.0 min LC-MS Run): XBridge C18 column (4.6×50 mm, 3.5μm, 40° C.); mobile phase: A=0.1% ammonia in water, B=acetonitrile;gradient: 0.0-8.0 min, 5%-95% B; flow rate=1.2 mL/min.

LC/MS Method C: (8.0 min LC-MS Run): XBridge C18 column (4.6×50 mm, 3.5μm, 40° C.); mobile phase: A=0.1% TFA in water, B=acetonitrile;gradient: 0.0-8.0 min, 5%-95% B; flow rate=1.2 mL/min.

LC/MS Method D: Agilent SB C18, 2.1×30 mm, 1.8 μm; mobile phase: A water(0.05% TFA), B CH₃CN (0.05% TFA); gradient: 3% B (0.3 min), followed by3-95% B (6.5 min), 95% B (1.5 min); flow rate: 0.4 mL/min; oventemperature 25° C.

LC/MS Method E: Acquity BEH C18, 2.1×50 mm, 1.8 μm; mobile phase: Awater (0.1% FA), B CH₃CN (0.1% FA); gradient: 3% B (0.4 min), followedby 3-95% B (7.5 min), 95% B (0.5 min); flow rate: 0.5 mL/min; oventemperature 25° C.

Abbreviations MeCN Acetonitrile

EtOAc Ethyl acetate

DCE Dichloroethane DCM Dichloromethane DIPEA Diisopropylethylamine DEADiethylamine

DMAP 4-dimethylaminopyridine

DMF N,N-Dimethylformamide DMSO Dimethylsulfoxide

FA Formic acidIPA Isopropyl alcoholTFA Trifluoroacetic acidEDCI 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochlorideHCl Hydrochloric acid

HPLC High Pressure Liquid Chromatography LCMS Liquid Chromatography MassSpectrometry MeOH Methanol

NMP N-methyl-2-pyrrolidoneRPHPLC Reverse phase high pressure liquid chromatographyRT Retention time

SFC Supercritical Fluid Chromatography THF Tetrahydrofuran TEATriethylamine Example 1

(S)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide

Step 1:(R,Z)-2-methyl-N-(1-(pyridin-2-yl)ethylidene)propane-2-sulfinamide

To a mixture of (R)-2-methylpropane-2-sulfinamide (105 g, 0.86 mol) and1-(pyridin-2-yl)ethanone (95 g, 0.78 mol) in DCM (1.5 L) was slowlyadded titanium(IV) ethoxide (322 mL, 1.57 mol) under a nitrogenatmosphere. The reaction mixture was heated to 40° C. for 16 h. Aftercooling to room temperature, sat. aq. NaHCO₃ (350 mL) was added andfiltered through a short pad of anhydrous Na₂SO₄, washed with DCM (3 L).The organic layer was concentrated in vacuo. The crude residue waspurified by silica gel chromatography (petroleum ether/EtOAc=5:1) togive the title compound (85 g, 48%) as a yellow solid. ¹H NMR (400 MHz,CDCl₃) δ 8.66 (d, J=4.4 Hz, 1H), 8.14 (d, J=8.0 Hz, 1H), 7.81-7.73 (m,1H), 7.43-7.33 (m, 1H), 2.88 (s, 3H), 1.34 (s, 9H).

Step 2: (S,Z)-ethyl5-(((R)-tert-butylsulfinyl)imino)-5-(pyridin-2-yl)-3-(trifluoromethyl)pentanoate

To a solution of(R,Z)-2-methyl-N-(1-(pyridin-2-yl)ethylidene)propane-2-sulfinamide (85g, 0.38 mol) in anhydrous THF (850 mL) at −78° C. was added lithiumdiisopropylamide (2.0 M, 199 mL, 0.40 mmol). The reaction mixture wasstirred at −78° C. for 2 h, ethyl 4,4,4-trifluorobut-2-enoate (67 g,0.40 mol) in anhydrous THF (100 mL) was added. The reaction mixture waswarmed up to 0° C. over 30 min period and stirred at 0° C. for 3 h. Thereaction was quenched with sat. aq. ammonium chloride (500 mL),extracted with EtOAc (1 L×2), washed with brine (500 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The crude residuewas purified by silica gel chromatography (petroleum ether/EtOAc=5:1) togive the title compound (47 g, 32%) as yellow oil. H NMR (400 MHz,CDCl₃) δ 8.67 (d, J=4.8 Hz, 1H), 8.00 (s, 1H), 7.81-7.74 (m, 1H),7.43-7.35 (m, 1H), 4.09-3.92 (m, 3H), 3.64-3.46 (m, 2H), 2.68 (d, J=6.0Hz, 2H), 1.36 (s, 9H), 1.17 (t, J=7.2 Hz, 3H).

Step 3: (S)-ethyl 5-oxo-5-(pyridin-2-yl)-3-(trifluoromethyl)pentanoate

To a solution of (S, Z)-ethyl5-(((R)-tert-butylsulfinyl)imino)-5-(pyridin-2-yl)-3-(trifluoromethyl)pentanoate(47 g, 0.12 mol) in EtOH (400 mL) was added aq. HCl (4.0 M, 150 mL, 0.60mol). The reaction mixture was stirred at 40° C. for 3 h. After coolingto room temperature, EtOAc (1 L) was added, washed with sat. aq. Na₂CO₃(500 mL×2), brine (500 mL), dried over anhydrous Na₂SO₄, filtered andconcentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=10:1) to give the title compound(31 g, 89%) as yellow oil. LCMS M/Z (M+H) 290.

Step 4: (3R)-1-(pyridin-2-yl)-3-(trifluoromethyl)pentane-1,5-diol

To a solution of lithium aluminium hydride (10 g, 0.27 mol) in anhydrousTHF (450 mL) at 0° C. was added (S)-ethyl5-oxo-5-(pyridin-2-yl)-3-(trifluoromethyl)pentanoate (26.3 g, 90.9 mmol)in anhydrous THF (50 mL) dropwise under a nitrogen atmosphere. Thereaction mixture was stirred at 0° C. for 1 h. The reaction was quenchedwith water (11 mL) and 15% aq. NaOH (11 mL), dried over anhydrous MgSO₄,filtered. The filtrate was concentrated in vacuo to give the titlecompound (13 g, 57%) as light yellow oil that required no furtherpurification. LCMS M/Z (M+H) 250.

Step 5: (R)-5-oxo-5-(pyridin-2-yl)-3-(trifluoromethyl)pentanal

To a mixture of (3R)-1-(2-pyridyl)-3-(trifluoromethyl)pentane-1,5-diol(12.0 g, 48.15 mmol) in N,N-dimethylformamide (240 mL) at 0° C. wasadded Dess-Martin periodinane (42.89 g, 101.11 mmol). The mixture wasstirred at room temperature for 16 h. The mixture was diluted with EtOAc(3 L), washed with sat. aq. Na₂CO₃ (1 L×2) and water (1 L×2), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether/EtOAc=5:1) togive the title compound(3R)-5-oxo-5-(2-pyridyl)-3-(trifluoromethyl)pentanal (7.8 g, 66%) asyellow oil. ¹H NMR (400 MHz, CDCl₃) δ 9.79 (s, 1H), 8.69 (d, J=4.4 Hz,1H), 8.09-8.02 (m, 1H), 7.91-7.83 (m, 1H), 7.55-7.49 (m, 1H), 3.73-3.59(m, 2H), 3.49-3.38 (m, 1H), 2.88-2.79 (m, 1H), 2.69-2.60 (m, 1H)

Step 6:(S)—N-(2,4-dimethoxybenzyl)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide

To a solution of (3R)-5-oxo-5-(2-pyridyl)-3-(trifluoromethyl)pentanal(992 mg, 4.05 mmol) and(S)-4-amino-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)chroman-7-sulfonamide(1.2 g, 2.53 mmol) in toluene (40 mL) was added titanium(IV)isopropoxide (1.87 mL, 6.32 mmol) under a nitrogen atmosphere. Thereaction mixture was stirred at room temperature for 3 h. Sodiumtriacetoxyborohydride (8.04 g, 37.93 mmol) was added to the mixture andstirred at room temperature for an additional 16 h. EtOAc (100 mL) wasadded and washed with water (50 mL×2), brine (50 mL). The organic layerwas dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Thecrude residue was purified by silica gel chromatography (DCM/EtOAc=2:1)to give the title compound (1.5 g, 54%) as a white solid. LCMS M/Z (M+H)688.

Step 7:(S)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide

A mixture of(S)—N-(2,4-dimethoxybenzyl)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide(1.5 g, 1.35 mmol) and formic acid (15 mL) was stirred at roomtemperature for 1 h. The mixture was concentrated in vacuo. The residuewas purified by reverse phase chromatography (acetonitrile 55-75%/0.225%formic acid in water) to give the title compound (427 mg, 59%) as awhite solid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 1H), 8.51 (d, J=4.8Hz, 1H), 8.25-8.24 (m, 1H), 7.82-7.76 (m, 1H), 7.66 (d, J=8.0 Hz, 1H),7.56 (d, J=10.8 Hz, 1H), 7.32-7.26 (m, 1H), 7.14 (d, J=6.0 Hz, 1H), 7.00(d, J=4.0 Hz, 1H), 4.28-4.21 (m, 1H), 3.90-3.78 (m, 2H), 3.56-3.52 (m,1H), 2.58-2.54 (m, 2H), 2.44-2.32 (m, 1H), 2.07-1.94 (m, 1H), 1.91-1.70(m, 4H), 1.53-1.51 (m, 1H). LCMS M/Z (M+H) 538.

Example 2

(S)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide

Step 1:

benzyl 2-(4-fluorophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate

To a solution of 4-methoxypyridine (10.0 g, 91.63 mmol) in anhydrous THF(250 mL) at −20° C. was slowly added benzyl carbonochloridate (17.01 mL,119 mmol) under a nitrogen atmosphere. The reaction mixture was stirredat room temperature for 1 h. (4-fluorophenyl)magnesium bromide in THF(1.0 M, 146.61 mL, 146.61 mmol) at −20° C. was added to the mixture andstirred at the same temperature for an additional 1 h. The mixture wasquenched with 3% aq. hydrogen chloride (40 mL) and extracted withtoluene (40 mL). The organic layer was washed with 4.5% aq. NaHCO₃ (40mL), dried over anhydrous Na₂SO₄, filtered and concentrated in vacuo.Isopropyl alcohol (15 mL) was added to the mixture and stirred at roomtemperature for 1 h. The solid was isolated by filtered. The filter cakewas washed with isopropyl alcohol (5 mL×3) and dried in vacuo to givethe title compound (14 g, 47%) as a white solid. ¹H NMR (400 MHz,DMSO-d₆) δ 8.06 (d, J=8.4 Hz, 1H), 7.42-7.30 (m, 5H), 7.27-7.22 (m, 2H),7.20-7.12 (m, 2H), 5.74 (d, J=7.2 Hz, 1H), 5.36-5.17 (m, 3H), 3.32-3.20(m, 1H), 2.62 (d, J=16.8 Hz, 1H). LCMS M/Z (M+H) 326.

Step 2:

benzyl 2-(4-fluorophenyl)-4-oxopiperidine-1-carboxylate

A mixture of benzyl2-(4-fluorophenyl)-4-oxo-3,4-dihydropyridine-1(2H)-carboxylate (14.0 g,43.03 mmol) and zinc powder (28.14 g, 430.33 mmol) in acetic acid (100mL) was stirred at room temperature for 24 h. The mixture was filteredand the filter cake was washed with acetic acid (30 mL×3). The filtratewas concentrated in vacuo. The crude residue was purified by silica gelchromatography (petroleum ether/EtOAc=3:1) to give the title compound(14 g, 99%) as colorless oil. LCMS M/Z (M+H) 328.

Step 3:

(trans)-benzyl2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate&(cis)-benzyl2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate

To a solution of benzyl 2-(4-fluorophenyl)-4-oxopiperidine-1-carboxylate(12.0 g, 36.66 mmol) in anhydrous THF (200 mL) at 0° C. was added(trifluoromethyl)trimethylsilane (19.06 mL, 47.66 mmol) andtetrabutylammonium fluoride in THF (1.0 M, 3.67 mL, 3.67 mmol). Thereaction mixture was stirred at room temperature for 16 h. Water (50 mL)was added and extracted with EtOAc (50 mL). The organic layer was driedover anhydrous Na₂SO₄, filtered and concentrated in vacuo. The cruderesidue was purified by silica gel chromatography (petroleumether/EtOAc=10:1) to give (trans)-benzyl2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylaterac-5B (3.4 g, less polar on TLC) as a white solid and (cis)-benzyl2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylaterac-5A (0.88 g, more polar on TLC) as a white solid. Trans-isomer: ¹HNMR (400 MHz, CDCl₃) δ 7.31-7.25 (m, 3H), 7.22-7.16 (m, 2H), 7.11-7.05(m, 2H), 7.03-6.96 (m, 2H), 5.15-4.97 (m, 3H), 4.33-4.25 (m, 1H),3.42-3.28 (m, 1H), 2.55 (s, 1H), 2.27-2.12 (m, 2H), 2.06-1.99 (m, 1H),1.97-1.86 (m, 1H). LCMS M/Z (M+H) 398. Cis-isomer: ¹H NMR (400 MHz,CDCl₃) δ 7.30-7.24 (m, 3H), 7.22-7.15 (m, 2H), 7.11-7.05 (m, 2H),7.03-6.95 (m, 2H), 5.15-4.97 (m, 3H), 4.35-4.22 (m, 1H), 3.41-3.29 (m,1H), 2.57 (s, 1H), 2.28-2.12 (m, 2H), 2.08-1.98 (m, 1H), 1.97-1.84 (m,1H). LCMS M/Z (M+H) 398.

Step 4:

(2S,4S)-benzyl2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate& (2R,4R)-benzyl2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate

(cis)-Benzyl2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate(0.88 g) was separated by using chiral SFC (Whelk-01 250 mm*30 mm, 10UM, Supercritical CO₂/MeOH+DEA=70/30; 70 ml/min) to give (2S,4S)-benzyl2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate(0.37 g, first peak) as a white solid and (2R,4R)-benzyl2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate(0.38 g, second peak) as a white solid.

Step 5:

(2S,4S)-2-(4-fluorophenyl)-4-(trifluoromethyl)piperidin-4-ol

To solution of benzyl(2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidine-1-carboxylate(1.2 g, 3.02 mmol) in EtOH (20 mL) was added 20% palladium hydroxide oncarbon (1.09 g). The mixture was stirred at room temperature for 1 hunder a hydrogen atmosphere (15 psi). The mixture was filtered and thefiltrate was concentrated in vacuo to give the title compound (700 mg,crude) as a white solid that required no further purification. ¹H NMR(400 MHz, CDCl₃) δ 7.37-7.35 (m, 2H), 7.04-7.00 (m, 2H), 4.02-3.98 (m,1H), 3.19-3.12 (m, 2H), 1.90-1.65 (m, 4H).

Step 6:(R)-7-(N-(2,4-dimethoxybenzyl)-N-(pyrimidin-4-yl)sulfamoyl)-6-fluorochroman-4-ylmethanesulfonate

To a solution of(R)—N-(2,4-dimethoxybenzyl)-6-fluoro-4-hydroxy-N-(pyrimidin-4-yl)chroman-7-sulfonamide(800 mg, 1.68 mmol) and triethylamine (0.7 mL, 5.05 mmol) in DCM (10 mL)at 0° C. was added methanesulfonic anhydride (586 mg, 3.36 mmol) in DCM(3 mL). The resulting mixture was stirred at room temperature for 2 h.The mixture was diluted with DCM (30 mL), washed with 10% aqueous citricacid (20 mL), sat. aq. NaHCO₃ (20 mL), brine (10 mL), dried overanhydrous Na₂SO₄, filtered and concentrated in vacuo to give the titlecompound (750 mg, crude) as a yellow solid that required no furtherpurification. ¹H NMR (400 MHz, CDCl₃) δ 8.80 (s, 1H), 8.47 (d, J=6.0 Hz,1H), 7.54 (d, J=6.0 Hz, 1H), 7.27-7.18 (m, 3H), 6.43-6.41 (m, 2H),5.75-5.73 (m, 1H), 5.27 (s, 2H), 4.42-4.38 (m, 1H), 4.31-4.25 (m, 1H),3.79 (s, 3H), 3.78 (s, 3H), 3.10 (s, 3H), 2.40-2.36 (m, 1H), 2.35-2.18(m, 1H).

Step 7:

(S)—N-(2,4-dimethoxybenzyl)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide&(R)—N-(2,4-dimethoxybenzyl)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide

To a solution of(2S,4S)-2-(4-fluorophenyl)-4-(trifluoromethyl)piperidin-4-ol (190 mg,0.72 mmol) and(R)-7-(N-(2,4-dimethoxybenzyl)-N-(pyrimidin-4-yl)sulfamoyl)-6-fluorochroman-4-ylmethanesulfonate (799 mg, 1.44 mmol) in EtOAc (4 mL) was addedN,N-diisopropylethylamine (0.6 mL, 3.61 mmol). The mixture was heated to80° C. for 16 h under a nitrogen atmosphere. After cooling to roomtemperature, the mixture was concentrated in vacuo. The residue waspurified by silica gel chromatography (petroleum ether/EtOAc=5:1) togive(R)—N-(2,4-dimethoxybenzyl)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide(70 mg, 13.5%, less polar on TLC) and(S)—N-(2,4-dimethoxybenzyl)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide(170 mg, 33%, more polar on TLC) as colorless oil. LCMS M/Z (M+H) 721.

Step 8:

(S)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide

A mixture of(S)—N-(2,4-dimethoxybenzyl)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide(300 mg, 0.42 mmol) and formic acid (5 mL) was stirred at roomtemperature for 1 h. The mixture was concentrated in vacuo. The residuewas purified by reverse phase chromatography (acetonitrile 40-70%/0.225%formic acid in water) to give the title compound (50 mg, 21%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) 8.56 (s, 1H), 8.25 (d, J=2.0 Hz, 1H),7.59-7.49 (m, 3H), 7.18-7.13 (m, 3H), 6.99 (s, 1H), 6.03 (s, 1H),4.27-4.24 (m, 1H), 3.96-3.93 (m, 1H), 3.82-3.79 (m, 1H), 3.67-3.63 (m,1H), 2.68-2.63 (m, 1H), 2.36-2.33 (m, 1H), 2.03-1.94 (m, 1H), 1.86-1.76(m, 4H), 1.68-1.65 (m, 1H). LCMS M/Z (M+H) 571.

Example 3

(S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide

Step 1:

(trans)-benzyl4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine-1-carboxylate &(cis)-benzyl4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine-1-carboxylate

To a solution of benzyl2-(4-fluorophenyl)-4-hydroxy-piperidine-1-carboxylate (20.0 g, 60.72mmol) in acetonitrile (200 mL) was added CuI (2.32 g, 12.16 mmol). Themixture was heated to 45° C. Then 2,2-difluoro-2-(fluorosulfonyl)aceticacid (21.64 g, 121.44 mmol) was added dropwise for 0.5 h. The mixturewas heated to 45° C. for an additional 2 h. After cooling to roomtemperature, the mixture was concentrated in vacuo. EtOAc (200 mL) wasadded, washed with brine (100 mL), dried over anhydrous Na₂SO₄, filteredand concentrated in vacuo. The residue was purified by silica gelchromatography (petroleum ether/EtOAc=5:1) to give(trans)-benzyl-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine-1-carboxylate(4.3 g, 19%, less polar on TLC) and (cis)benzyl-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine-1-carboxylate (6g, crude, more polar on TLC) as colorless oil. The cis-product (6 g,crude) was re-purified by reverse phase chromatography (acetonitrile55-85%/0.225% formic acid in water) to give(cis)-benzyl-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine-1-carboxylate(3 g, 13%) as colorless oil. Trans-isomer: ¹H NMR (400 MHz, CDCl₃) δ7.44-7.28 (m, 5H), 7.23-7.16 (m, 2H), 7.09-7.01 (m, 2H), 6.45-6.03 (m,1H), 5.67 (s, 1H), 5.71-5.62 (m, 1H), 5.71-5.62 (m, 1H), 5.22 (s, 2H),4.40-4.18 (m, 2H), 2.89-2.76 (m, 1H), 2.73-2.61 (m, 1H), 2.04-1.92 (m,2H), 1.75-1.62 (m, 1H). LCMS M/Z (M+H) 380. Cis-isomer: ¹H NMR (400 MHz,CDCl₃) δ 7.37-7.24 (m, 5H), 7.21-7.14 (m, 2H), 7.03-6.95 (m, 2H),6.19-5.79 (m, 1H), 5.45-5.35 (m, 1H), 5.20-5.12 (m, 2H), 4.66-4.59 (m,1H), 4.19-4.08 (m, 1H), 3.37-3.25 (m, 1H), 2.57-2.47 (m, 1H), 2.22-2.13(m, 1H), 1.97-1.78 (m, 2H). LCMS M/Z (M+H) 380.

Step 2:

(2R,4S)-benzyl4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine-1-carboxylate&(2S,4R)-benzyl4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine-1-carboxylate

(Cis)-benzyl-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine-1-carboxylate(3.0 g, 7.91 mmol) was separated by chiral SFC (Chiralpak OJ (250 mm*50mm, 10 um), Supercritical CO₂/IPA+0.1% NH₄OH=85/15; 180 mL/min) to give(2R,4S)-benzyl4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine-1-carboxylate (1.2 g,40%, first peak) and (2S,4R)-benzyl4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine-1-carboxylate (1.3 g,43%, second peak) as yellow oil. LCMS M/Z (M+H) 380.

Step 3:

(2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine

To a solution of (2S,4R)-benzyl4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine-1-carboxylate (1.3 g,3.43 mmol) in MeOH (20 mL) was added 20% palladium hydroxide on carbon(500 mg). The mixture was stirred at room temperature for 1 h under ahydrogen atmosphere (15 psi). The mixture was filtered and the filtratewas concentrated in vacuo to give the title compound (800 mg, 95%) as awhite solid. LCMS M/Z (M+H) 246

Step 4:

(S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-N-(2,4-dimethoxybenzyl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide&(R)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-N-(2,4-dimethoxybenzyl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide

To a solution of(2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidine (300 mg, 1.23mmol) and N,N-diisopropylethylamine (1.01 mL, 6.12 mmol) in ethylacetate (12 mL) was added(R)-7-(N-(2,4-dimethoxybenzyl)-N-(pyrimidin-4-yl)sulfamoyl)-6-fluorochroman-4-ylmethanesulfonate (1.31 g, 2.45 mmol). The mixture was heated to 80° C.for 16 h under a nitrogen atmosphere. After cooling to room temperature,the mixture was concentrated in vacuo. The residue was purified byprep-TLC (50% EtOAc in petroleum ether) to give(S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-N-(2,4-dimethoxybenzyl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide(155 mg, 18%, more polar on TLC) and(R)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-N-(2,4-dimethoxybenzyl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide(160 mg, 19%, less polar on TLC) as white solid. LCMS M/Z (M+H) 703.

Step 5:

(S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide

A mixture of(S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-N-(2,4-dimethoxybenzyl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide(155 mg, 0.22 mmol) and formic acid (3 mL) was stirred at roomtemperature for 1 h. The mixture was concentrated in vacuo. The residuewas purified by reverse phase chromatography (acetonitrile 30-60%/0.225%formic acid in water) to give the title compound (75 mg, 62%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.57 (s, 1H), 8.31-8.20 (m, 1H),7.52-7.42 (m, 2H), 7.19 (d, J=10.4 Hz, 1H), 7.15-7.06 (m, 3H), 7.03-6.95(m, 1H), 6.89-6.48 (m, 1H), 4.22-4.08 (m, 3H), 3.90-3.75 (m, 2H),2.72-2.67 (m, 1H), 2.28-2.17 (m, 1H), 2.02-1.90 (m, 3H), 1.83-1.73 (m,1H), 1.68-1.54 (m, 2H). LCMS M/Z (M+H) 553.

Example 4

(S)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide

Step 1:

(2S,3R)-tert-butyl2-acetyl-5-oxo-3-(3-(trifluoromethyl)phenyl)pentanoate

A mixture of (E)-3-(3-(trifluoromethyl)phenyl)acrylaldehyde (1.27 g,6.32 mmol) in water (12 mL) was added(S)-2-(bis(3,5-bis(trifluoromethyl)phenyl)((trimethylsilyl)oxy)methyl)pyrrolidine(378 mg, 0.63 mmol) and tert-butyl 3-oxobutanoate (1.0 g, 6.32 mmol).The reaction mixture was stirred at room temperature for 16 h. Themixture was diluted with EtOAc (100 mL), washed with water (50 mL) andbrine (50 mL), dried over anhydrous Na₂SO₄, filtered and concentrated invacuo to give the title compound (2.25 g, crude) as a yellow oil. ¹H NMR(400 MHz, CDCl₃) δ 9.64-9.59 (m, 1H), 7.56-7.38 (m, 4H), 4.10-4.01 (m,1H), 3.87-3.84 (m, 1H), 2.96-2.76 (m, 2H), 2.06-2.04 (m, 3H), 1.16-1.12(m, 9H).

Step 2:

(R)-5-oxo-3-(3-(trifluoromethyl)phenyl)hexanal

A solution of (2S,3R)-tert-butyl2-acetyl-5-oxo-3-(3-(trifluoromethyl)phenyl)pentanoate (1.0 g, 2.79mmol) in 2,2,2-trifluoroacetic acid (5 mL) and dichloromethane (5 mL)was stirred at room temperature for 1 h. The reaction was quenched withNaHCO₃ (50 mL), extracted with EtOAc (50 mL). The organic layer wasdried over anhydrous Na₂SO₄, filtered and concentrated in vacuo to givethe title compound (720 mg, crude) as yellow oil.

Step 3:

(S)—N-(2,4-dimethoxybenzyl)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide

To a solution of (R)-5-oxo-3-(3-(trifluoromethyl)phenyl)hexanal (327 mg,1.26 mmol) and(S)-4-amino-N-(2,4-dimethoxybenzyl)-N-(1,2,4-thiadiazol-5-yl)chroman-7-sulfonamide(400 mg, 0.84 mmol) in toluene (10 mL) was added titanium(IV)isopropoxide (0.62 mL, 2.1 mmol) under a nitrogen atmosphere. Thereaction mixture was stirred at room temperature for 3 h. Sodiumtriacetoxyborohydride (1.79 g, 8.42 mmol) was added to the mixture andstirred at room temperature for an additional 16 h. EtOAc (100 mL) wasadded and washed with water (50 mL×2), brine (50 mL). The organic layerwas dried over anhydrous MgSO₄, filtered and concentrated in vacuo. Thecrude residue was purified by reverse phase chromatography (acetonitrile75-100%/0.05% ammonia hydroxide in water) to give the title compound (50mg, 8%) as a white solid. ¹H NMR (400 MHz, CDCl₃) δ 8.78 (s, 1H), 8.44(d, J=5.6 Hz, 1H), 7.52-7.44 (m, 3H), 7.43-7.39 (m, 3H), 7.30 (d, J=5.2Hz, 1H), 7.23 (d, J=8.0 Hz, 1H), 6.45-6.39 (m, 2H), 5.31 (s, 2H),4.52-4.45 (m, 1H), 4.19-4.04 (m, 2H), 3.81 (s, 3H), 3.78 (s, 3H),2.95-2.87 (m, 1H), 2.78-2.58 (m, 3H), 2.30-2.18 (m, 1H), 2.15-2.07 (m,1H), 1.94-1.74 (m, 3H), 1.53-1.41 (m, 1H), 0.74 (s, 3H). LCMS M/Z (M+H)701.

Step 4:

(S)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide

A mixture of(S)—N-(2,4-dimethoxybenzyl)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide(50 mg, 0.07 mmol) and formic acid (1 mL) was stirred at roomtemperature for 1 h. The mixture was concentrated in vacuo. The residuewas purified by reverse phase chromatography (acetonitrile 26-56%/0.225%formic acid in water) to give the title compound (26 mg, 67%) as a whitesolid. ¹H NMR (400 MHz, DMSO-d₆) δ 8.54 (s, 1H), 8.25 (d, J=6.0 Hz, 1H),7.61-7.51 (m, 4H), 7.49-7.40 (m, 1H), 7.17 (d, J=6.0 Hz, 1H), 6.98 (d,J=6.4 Hz, 1H), 4.46-4.38 (m, 1H), 4.24-4.08 (m, 2H), 2.94-2.83 (m, 1H),2.78-2.64 (m, 3H), 2.15-2.01 (m, 2H), 1.85-1.67 (m, 3H), 1.49-1.36 (m,1H), 0.71 (s, 3H). LCMS M/Z (M+H) 551.

Example 5: Tritiated Compound Binding to Membranes Isolated from Cellsthat Heterologously Express hNav1.7 and the β1 Subunit

Preparation of membranes containing recombinantly expressed sodiumchannels: Frozen recombinant cell pellets were thawed on ice and dilutedto 4 times the cell pellet weight with ice cold 50 mM Tris HCl, pH 7.4buffer. The cell suspensions were homogenized on ice using a motorizedglass dounce homogeniser. Homogenates were further diluted 8.4 timeswith ice cold 50 mM Tris HCl, pH 7.4 buffer and then centrifuged at200×g at 4° C. for 15 min. The supernatants were collected andcentrifuged at 10000×g at 4° C. for 50 min. The pellets were thenre-suspended in 100 mM NaCl, 20 mM Tris HCl, pH 7.4 buffer containing 1%v/v protease inhibitors (Calbiochem) and re-homogenized on ice. Thehomogenized membranes were then processed through a syringe equippedwith a 26 gauge needle. Protein concentrations were determined byBradford Assay and the membranes were stored at −80° C.

Radioligand Binding Studies: Saturation experiments. A competitiveNaV1.7 inhibitor having a methyl group was tritiated. Three tritiumswere incorporated in place of methyl hydrogens to generate [³H]compound.Binding of this radioligand was performed in 5 mL borosilicate glasstest tubes at room temperature. Binding was initiated by addingmembranes to increasing concentrations of [³H]compound in 100 mM NaCl,20 mM Tris HCl, pH 7.4 buffer containing 0.01% w/v bovine serum albumin(BSA) for 18 h. Non-specific binding was determined in the presence of 1M unlabeled compound. After 18 h, the reactants were filtered throughGF/C glass fiber filters presoaked in 0.5% w/v polyethylene imine.Filters were washed with 15 mL ice cold 100 mM NaCl, 20 mM Tris HCl,pH7.4 buffer containing 0.25% BSA to separate bound from free ligand.[³H]compound bound to filters was quantified by liquid scintillationcounting.

Competitive binding experiments: Binding reactions were performed in96-well polypropylene plates at room temperature for 18 h. In 360 μL,membranes were incubated with 100 pM [3H]compound and increasingconcentrations of Test Compound. Non-specific binding was defined in thepresence of 1 M unlabeled compound. Reactions were transferred andfiltered through 96-well glass fiber/C filter plates presoaked with 0.5%polyethylene imine. The filtered reactions were washed 5 times with 200μL ice cold buffer containing 0.25% BSA. Bound radioactivity wasdetermined by liquid scintillation counting.

Data Analysis: For saturation experiments, non-specific binding wassubtracted from total binding to provide specific binding and thesevalues were recalculated in terms of pmol ligand bound per mg protein.Saturation curves were constructed and dissociation constants werecalculated using the single site ligand binding model:Beq=(Bmax*X)/(X+Kd), where Beq is the amount of ligand bound atequilibrium, Bmax is the maximum receptor density, Kd is thedissociation constant for the ligand, and X is the free ligandconcentration. For competition studies percent inhibition was determinedand IC₅₀ values were calculated using a 4 parameter logistic model (%inhibition=(A+((B−A)/(1+((x/C){circumflex over ( )}D)))) using XLfit,where A and B are the maximal and minimum inhibition respectively, C isthe IC₅₀ concentration and D is the (Hill) slope.

Representative compounds, when tested in this model or anotherrepresentative model of inhibition, demonstrated in vitro Na_(V)1.7inhibition as set forth in Table 1 below.

Example 6: In Vivo Pharmacokinetic Experiments (Compound Clearance inRats)

In vivo clearance (CL_(p)) of certain compounds was measured in order toevaluate whether these compounds were likely to be good candidates fordevelopment. Male rats were housed at controlled temperature andhumidity in an alternating 12 hr light/dark cycle with access to foodand water ad libitum. All in vivo studies were performed in accordancewith Institutional Animal Care and Use Committee guidelines and inharmony with the Guide for Laboratory Animal Care and Use. Rats wereadministered IV administration of compound. Plasma was harvested fromblood samples that were collected from each animal at various timepointsfollowing the administration of compound. Plasma concentration ofcompound was determined by mass spectrometer, and pharmacokineticanalysis was performed using non-compartmental method using PhoenixWinNonlin. Following oral administration, percent bioavailability wasdetermined for each animal by dividing the dose-normalized area underthe plasma concentration-time curve from time 0 to the last measuredconcentration (AUC0-tlast) obtained following each oral dose by the meandose-normalized AUC0-tlast of the animals dosed by IV injection.

Representative compounds, when tested in this model, demonstrated thepharmacokinetic (“PK”) property (CL_(p)) as set forth in Table 1 below.A compound demonstrating a CL_(p) value of about 40 mL/min/kg or less inthe model of Example 6 is considered to be low to moderately clearedfrom the body, meaning that there may be reasonable exposure of acompound to a subject to be treated for a disease or disorder asprovided herein. CL_(p) values above about 40 mL/min/kg in Example 6 areconsidered to be highly cleared from the body after administration of acompound to a subject, meaning that the exposure may be insufficient tobe treated for a disease or disorder as provided herein. Each of thecompounds of Table 1 demonstrated good stability as evidenced by CL_(p)values less than 30 mL/min/kg.

TABLE 1 Nav1.7 inhib. in vitro PK (CL_(p), rat) Example Structure (μM)(mL/min/kg) 1

0.0005 <30 2

0.0005 <30 3

0.0022 <30 4

0.0034 <30

Table 2 shows additional representative compounds identified as potentNa_(V)1.7 inhibitors, but which surprisingly demonstrated poorpharmacokinetic properties (i.e., CL_(p)) in the method described inExample 6 above.

TABLE 2 Nav1.7 inhib. Reference in vitro PK (CL_(p), rat) CompoundStructure (μM) (mL/min/kg) A

0.0011 >60 B

<0.0005 >60 C

0.0008 >60 D

0.011 >60 E

0.0026 >60 F

0.0088 >60

All of the U.S. patents, U.S. patent application publications, U.S.patent applications, foreign patents, foreign patent applications andnon patent publications referred to in this specification areincorporated herein by reference in their entireties.

Although the foregoing invention has been described in some detail tofacilitate understanding, it will be apparent that certain changes andmodifications may be practiced within the scope of the appended claims.Accordingly, the described embodiments are to be considered asillustrative and not restrictive, and the invention is not to be limitedto the details given herein, but may be modified within the scope andequivalents of the appended claims.

We claim:
 1. A method of treating a disease or condition in a mammalselected from the group consisting of pain, depression, cardiovasculardiseases, respiratory diseases, and psychiatric diseases, andcombinations thereof, wherein the method comprises administering to themammal a therapeutically effective amount of a compound selected fromthe group consisting of:(S)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;(S)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;(S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide;and(S)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;or a pharmaceutically acceptable thereof.
 2. The method of claim 1,wherein said disease or condition is selected from the group consistingof acute pain, chronic pain, neuropathic pain, inflammatory pain, acutepain, chronic pain, visceral pain, cancer pain, chemotherapy pain,trauma pain, surgical pain, post-surgical pain, childbirth pain, laborpain, neurogenic bladder, ulcerative colitis, persistent pain,peripherally mediated pain, centrally mediated pain, chronic headache,migraine headache, sinus headache, tension headache, phantom limb pain,dental pain, peripheral nerve injury or a combination thereof.
 3. Themethod of claim 1, wherein said disease or condition is selected fromthe group consisting of pain associated with HIV, HIV treatment inducedneuropathy, trigeminal neuralgia, post-herpetic neuralgia, eudynia, heatsensitivity, tosarcoidosis, irritable bowel syndrome, Crohns disease,pain associated with multiple sclerosis (MS), amyotrophic lateralsclerosis (ALS), diabetic neuropathy, peripheral neuropathy, arthritis,rheumatoid arthritis, osteoarthritis, atherosclerosis, paroxysmaldystonia, myasthenia syndromes, myotonia, malignant hyperthermia, cysticfibrosis, pseudoaldosteronism, rhabdomyolysis, hypothyroidism, bipolardepression, anxiety, schizophrenia, sodium channel toxin relatedillnesses, familial erythromelalgia, primary erythromelalgia, familialrectal pain, cancer, epilepsy, partial and general tonic seizures,restless leg syndrome, arrhythmias, fibromyalgia, neuroprotection underischaemic conditions cause by stroke or neural trauma, tach-arrhythmias,atrial fibrillation and ventricular fibrillation.
 4. A method oftreating pain in a mammal by the inhibition of ion flux through avoltage-dependent sodium channel in the mammal, wherein the methodcomprises administering to the mammal a therapeutically effective amountof a compound selected from the group consisting of:(S)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;(S)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;(S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide;and(S)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;or a pharmaceutically acceptable thereof.
 5. A method of decreasing ionflux through a voltage-dependent sodium channel in a cell in a mammal,wherein the method comprises contacting the cell with a compoundselected from the group consisting of:(S)-6-fluoro-4-((2S,4R)-2-(pyridin-2-yl)-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;(S)-6-fluoro-4-((2S,4S)-2-(4-fluorophenyl)-4-hydroxy-4-(trifluoromethyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;(S)-4-((2S,4R)-4-(difluoromethoxy)-2-(4-fluorophenyl)piperidin-1-yl)-6-fluoro-N-(pyrimidin-4-yl)chroman-7-sulfonamide;and(S)-6-fluoro-4-((2R,4R)-2-methyl-4-(3-(trifluoromethyl)phenyl)piperidin-1-yl)-N-(pyrimidin-4-yl)chroman-7-sulfonamide;or a pharmaceutically acceptable thereof.